Method For Treatment Of HIV And Diseases Of Immune Dysregulation

ABSTRACT

This invention discloses cannabinoid derivatives and pharmaceutical uses thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of U.S. patent application Ser. No.11/978,318, filed Oct. 29, 2007, which is a continuation-in-part of U.S.patent application Ser. No. 11/327,693 (now Abandoned), filed on Jan. 5,2006, which is a continuation of U.S. patent application Ser. No.10/328,242 (now U.S. Pat. No. 7,105,685), filed Dec. 22, 2002, which isa continuation of application Ser. No. 09/928,683 (now U.S. Pat. No.6,566,560) filed on Aug. 13, 2001, which is a continuation-in-part ofU.S. patent application Ser. No. 09/533,386 (now. U.S. Pat. No.6,274,635) filed on Mar. 22, 2000, which claims priority to U.S.provisional patent application Nos. 60/125,674 and 60/151,595 filed onMar. 22, 1999 and Aug. 30, 1999, respectively.

BACKGROUND OF THE INVENTION

The retroviral Human Immunodeficiency Viruses (HIV) 1 and 2 are the mostcommon causative agents of AIDS. Through a portion of a viral envelopeprotein (gp120), HIV binds specifically and with high affinity to theCD4 molecule on T-lymphocytes. Following binding, the virus fuses withthe cell membrane and is internalized. Within the cell, it produces areverse transcriptase which transcribes its genomic RNA to DNA. Thereverse HIV transcript is then integrated into the cellular DNA where itexists for the life of the cell as a “provirus.” The provirus can remainlatent for an indefinite period of time, or it can be “activated” totranscribe mRNA and genomic RNA, leading to protein synthesis, assembly,new virion formation, budding of virus from the cell surface, and celldeath.

While the precise events triggering activation are poorly understood,they appear to lead to liberation or production of endogenous cellularfactors that interact with the HIV genome to promote translation. Inthis regard, binding of cellular SP1 to the HIV promoter (which containsseveral tandem SP1 consensus binding sites) is needed for high-leveltranscription of the latent HIV genome. Additionally, NFκB functions asa potent transcriptional activator when it binds to one or two(depending on the HIV strain) consensus binding sites in the HIVenhancer, which is adjacent to the promoter. The transcription factorsCREB/ATF, NF-AT, and AP1 also potentiate HIV transcription. As for allretroviruses, the structural and enzymatic gag, pol and env geneproducts are produced when the provirus is activated. HIV firsttranscribes gag-pol as a fusion protein which is ultimately cleaved bythe HIV protease enzyme to yield the (nature viral proteins. HIV alsoemploys additional regulatory proteins (specifically the tat and revgene products) as transcriptional enhancers to induce high levels ofgene expression. Nef is another HIV gene that modulates viralreplication levels.

While the set of factors triggering active viral replication remainsonly partially understood, some of them include heat shock, ultravioletradiation, regulatory proteins of other (e.g., superinfecting) viruses,inflammatory cytokines (e.g., IL1, IL2, IL4, IL6, IL10, Tumor NecrosisFactor a (TNFα), Platelet Activating Factor, Interferon y (IFNγ)), andNitric Oxide. Many of these factors are T-cell activators (e.g., theyprecipitate cell cycling and clonal expansion of T-cell populations),and they are released by many B-cells in direct response to infectiousagents (such as HIV). Such factors also trigger intracellular signalingevents promoting the production of NFκB and its dissociation from itsinhibitor (IkB). Active NFκB is a DNA binding protein activating thetranscription of many cellular genes, and also the HIV genome. In thisregard, cytokines such as TNF α and IL-1 augment NFκB activity incultured T-cells.

Some cells harboring the provirus express HIV gp41, gp120, and possiblyother viral proteins, presumably through basal levels of transcriptionfrom the proviral genome. While a host immune response is mountedagainst such HIV proteins, due in part to the high degree of mutabilityof such proteins and their varied glycosylation patterns, such immuneresponse usually is incomplete, resulting in a pool of latent virus thateffectively avoids immune surveillance. Additionally, the presence ofHIV gp120 in the membranes of infected cells can mediate fusion eventsbetween infected cells and non-infected antigen-presenting cells (e.g.,dendritic cells) via a reaction similar to that by which the virusenters uninfected cells. Rather than destroying infected cells, as mightbe expected for a cellular immune response, such fusion events typicallylead to the formation of short-lived multinucleated syncytial “giantcells,” which actually facilitate viral replication. In this regard,while latently-infected monocytes and T-lymphocytes normally arequiescent and have no active NFκB, other cells (e.g., dendritic cells)normally contain high levels of active NFκB. However, dendritic cells donot produce SP1, while T-cells and monocytes express Sp1 in active form.Formation of syncytia between infected T-cells and dendritic cells,thus, brings active-NFκB and SP 1 into the same cell, facilitatingtranscription of the HIV genome.

The viral life cycle ends when mature HIV is “budded” from the hostcell, retaining some amount of cell membrane as part of its envelope.Oftentimes, these budding events are localized to areas of the cellmembrane where intracellular adhesion molecules (ICAMs) and othersurface receptors coalesce during the cell's activation process. Becausesuch proteins localize to regions of intercellular contact, thisphenomenon (known as polar capping or polarization) can help spread theviral infection by “focusing” viral budding to an adjacent cell or infacilitating syncytia formation. Moreover, liberated virions oftencontain some membrane-bound ICAMs (e.g., ICAM-1), and such viruses canbind to cells (e.g., peripheral blood mononuclear cells) throughinteractions not involving the gp120-CD4 interaction. Such ICAM-¹⁺ HIVviruses are more infective than ICAM-1⁻ HIV, and since they are cloakedwith the host animal's glycoproteins, they are much less likely to beneutralized by circulating host antibodies. HIV can augment productionof cell adhesion molecules such as ICAM-1 by precipitating thephosphorylation of STAT1α, which binds to the ICAM-1 gene enhancer andpromotes SP1-dependent transcription. Interestingly, inflammatorycytokines (e.g., IFNγ) also precipitate phosphorylation of STAT1α, andthe gene contains consensus binding cites for some of the sametranscription factors involved in HIV replication, notably NFκB.

The presence of latent pools of HIV within quiescent cells, the highmutability of HIV proteins and their relative invisibility to immunesurveillance, and the ability of the virus to alter its tropism byacquiring ICAMs all permit the virus to replicate in the face of anaggressive host immune response. Over time, the virus gradually subvertsand progressively destroys the very system relied on to ward offinfections. This progression of viral persistence and replication is HIVdisease, and is marked by dysregulation of cytokine signaling,particularly in the lymphatic system, and ultimate destruction of lymphnodes. When HIV disease has progressed to the point where the host'simmune system becomes so incapacitated that it is unable to ward offopportunistic diseases (e.g., bacteria, fungi, neoplasms, etc.), AIDSdevelops. Many patients begin to develop AIDS symptoms when theirCD4+T-cell count drops to about 200 (most healthy adults have aCD4+T-cell count of about 1000.

To prevent the development of AIDS, many current therapies focus onhalting viral life cycle events, typically by directly targeting viralproteins. For example, gp120 anti-bodies have been produced in anattempt to block initial cell infection. However, due in part to theability of the virus to spread by syncytia or direct cell-to-cellcontact and its ability to acquire ICAM molecules, such attempts havemet with mixed results. Other therapies employ inhibitors of HIVprotease to block the formation of mature rep and cap from the rep-cappreprotein. Still other regimens employ combinations of antiviralcompounds, aimed at inhibiting or attenuating viral enzymes. It has beenestimated, however, that spontaneous mutations arise in HIV genes oncein about 10⁴ replications (Perelson et al., Science, 271, 1582-86(1996)). Given that the virus typically undergoes about 10¹⁰replications each day, resistance to agents acting directly againstviral proteins is not uncommon. Moreover, many regimens require apatient to adhere to very a strict dosing schedule involving scores ofpills each day. Failure of patients to comply with such regimens adds tothe failure rate of antiviral therapy. In light of these problems, thereis a need for new methods, compounds, and compositions for attenuatingthe progression of HIV disease and other immune dysfunctions.

Many thousands of people are diagnosed with cancer and other neoplasticdisorders each year, and although advances have been made in cancertherapy, the existing treatments are not successful in many cases. Forexample, many anticancer drugs administered to patients often have toxiceffects on non-cancerous cells in the patient's body. Moreover, manyneoplastic cells whose growth can be inhibited by certain drugssometimes become resistant to those drugs. Of course, responsive tumorsrepresent only a small fraction of the various types of neoplasticdisease and, notably, there are relatively few drugs highly activeagainst solid tumors such as ovarian cancer, breast cancer, lung cancerand the like. Thus, patients with many types of malignancies remain atsignificant risk for relapse and mortality. As such, there exists acontinuing need for agents that inhibit neoplastic growth, especiallysolid tumor growth.

SUMMARY OF THE INVENTION

The present invention provides a method, compounds, and compositions fortreating a disease associated with immune dysfunction. In accordancewith the method, a pharmacologically-acceptable composition including atleast one resorcinol derivative compound selected from the group ofcompounds consisting of resorcinols, cannabinol derivatives, cannabidiolderivatives, cannabigerol derivatives, cannabichromene derivatives, andcombinations thereof is administered to a patient under conditionssufficient to attenuate the dysfunction within the immune system. Theinvention also provides an antiviral cannabinol derivative that can beused in the inventive method. The invention also provides a (preferablyalkylated) resorcinol derivative and a method of using the resorcinolderivative to attenuate the growth of a neoplasm. The method andcompound are useful for treating diseases of the immune system, such asHIV disease and neoplastic disorders. These and other advantages of thepresent invention, as well as additional inventive features, will beapparent from the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 exemplarily demonstrates the antiviral activity of severalcompounds according to the method described herein.

FIG. 2 exemplarily demonstrates the antineoplastic activity of compoundsaccording to Formula 1 described herein.

FIG. 3 exemplarily illustrates a summary of EpiVaginal tissue viabilityfollowing systemic exposure to the test compounds for 24 hrs.

FIG. 4 exemplarily illustrates a summary of EpiVaginal tissue viabilityfollowing the systemic exposure to test compounds for 7 days.

FIG. 5 exemplarily illustrates a summary of TEER measurements followinga 24 hr exposure of test compounds to EpiVaginal tissues.

FIG. 6 exemplarily illustrates a summary of TEER measurements followinga 7 day exposure period of test compounds to EpiVaginal tissues.

FIG. 7 exemplarily illustrates the effect of cannabinoids on tissuethickness following exposure of test compounds to EpiVaginal tissue for7 days.

FIG. 8 exemplarily illustrates TEER measurements following exposure oftest compounds to EpiVaginal tissues for 24 hrs.

FIG. 9 exemplarily illustrates tissue viability and TEER measurementsfollowing 7 day exposure of the test compounds to the EpiVaginaltissues.

FIG. 10 exemplarily illustrates the thickness of EpiVaginal tissuescultured in a medium supplemented with cannabinoid JWH 015 at aconcentration of 100 μM for 7 days.

FIG. 11 exemplarily illustrates the thickness of EpiVaginal tissuescultured in a medium supplemented with cannabinoid JWH 015 at aconcentration of 10 nM for 7 days.

FIG. 12 exemplarily illustrates the thickness of EpiVaginal tissuescultured in a medium supplemented with cannabinoid L-759,656 at aconcentration of 100 μM for 7 days.

FIG. 13 exemplarily illustrates the thickness of EpiVaginal tissuescultured in a medium supplemented with cannabinoid L-759,656 at aconcentration of 10 nM for 7 days.

FIG. 14 exemplarily illustrates the thickness of EpiVaginal tissuescultured in a medium supplemented with cannabinoid L-759,633 at aconcentration of 100 μM for 7 days.

FIG. 15 exemplarily illustrates the thickness of EpiVaginal tissuescultured in a medium supplemented with cannabinoid L-759,633 at aconcentration of 10 nM for 7 days.

FIG. 16 exemplarily illustrates the thickness of EpiVaginal tissuescultured in a medium supplemented with cannabinoid AM 630 at aconcentration of 100 μM for 7 days.

FIG. 17 exemplarily illustrates the thickness of EpiVaginal tissuescultured in a medium supplemented with cannabinoid AM 630 at aconcentration of 10 nM for 7 days.

FIG. 18 exemplarily illustrates the thickness of EpiVaginal controltissues (phosphate buffered saline (PBS)) cultured in a medium for 7days.

FIGS. 19-22 exemplarily illustrate the expression levels of thecannabinoid receptors, CB1 and CB2, in a VEC-100 tissue model throughthe use of RT PCR and effect of three test compounds on the expressionof these receptors.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the invention provides a method for treating a diseaseassociated with immune dysfunction. In accordance with the method, apharmacologically-acceptable composition including at least one compoundselected from the group of compounds consisting of resorcinolderivatives, cannabinol derivatives, cannabidiol derivatives,cannabigerol derivatives, and combinations thereof is administered to apatient under conditions sufficient to attenuate the dysfunction withinthe immune system.

The inventive method is particularly effective in combating HIV diseasein humans, SIV disease in non-human primates, or FIV in feline animals.Without being bound by any particular theory, it is believed that theinventive method promotes quiescence of both actively- andlatently-infected T-cells, monocytes, and macrophages, potentiallythrough a variety of complementing mechanisms. The combination of theseeffects can attenuate the ability of HIV to replicate in a host immunesystem. Absent replication, uninfected components of the immune systemare better able to clear latently-infected cells from the patient, andfewer mutation events occur. Additionally, by attenuating HIVreplication, the method can reduce the probability of interpersonaltransmission, (e.g., perinatal or sexual transmission). Indeed,applications of the inventive method in which the composition isadministered to mucosal tissue (e.g. vaginal or rectal tissue), canretard the uptake of the virus through such tissues, thus reducing theincidence of primary infection. Thus, the invention provides a method ofpreventing the transmission of HIV. Furthermore, the method can guardagainst secondary conditions often attending HIV infection, such asdestruction of lymphatic structure, CNS disease, opportunistic diseases,neoplasms, and the AIDS Wasting Syndrome.

Treatment of HIV disease can be assessed by monitoring the attenuationof its symptoms in response to the continued application of theinventive method. For example, while most healthy adult humans have aCD4+T-cell count from between about 800 to about 1200, that of HIV+patients steadily declines, as discussed above. Therefore, the inventivemethod pertains to increasing, or attenuating the decrease of, thenumber of CD4+T-cells (typically by assaying for the CD4+/CD8+ratio)within an HIV+ patient. For example, through periodic measurements, therate at which a given patient's CD4+T-cells is declining can be assessedboth before and after commencement of therapy in accordance with theinventive method. Favorable application of the method at least slowsthis rate of decrease, and preferably potentiates actual gain inCD4+cell number. Similarly, the method can decrease, or attenuate theincrease of, viral load (i.e., the titer of circulating HIV) within apatient. Favorable response to the treatment can also be monitored bymeasuring leukocyte adhesion, lymphocyte trafficking, andmonocyte/macrophage mobility (i.e., a chemotaxis assay).

In one embodiment, at least one compound within thepharmacologically-acceptable composition can be a resorcinol derivative(e.g., a 5-alkyl or 3-alkyl or -acyl resorcinol). Such compounds areadvantageous for use in the inventive method as they generally exhibitlow cytoxicity (see, e.g., U.S. Pat. No. 5,859,067). Exemplaryresorcinols can have the following formula:

wherein, —COR¹, —COR³, and/or —COR⁶, respectively, and preferably R³ is—COR³, and wherein R can otherwise be as follows:

R¹ is:

-   -   a) H,    -   b) a C₁₋₄ alkyl group or ester thereof,    -   c) COOH,    -   d) OH,    -   e) a O—C₁₋₅ alkyl (preferably OCH₃) or alkanoyl, optionally        substituted by mono- or dimethylamino or ethylamino groups,    -   f) a O—CO—C₃₋₁₀ alkyl group containing a carboxyl or amino        group,    -   g)

-   -   -   wherein n=1 to 8

    -   h) a p-aminobenzyl group or a C₁₋₇ aminoalkyl group or an        organic or mineral acid addition salt thereof, an isocyanate or        isothiocyanate derivative of the p-aminobenzyl or aminoalkyl        group, a carboxyl terminated derivative of the aminoalkyl group        having from 1 to 7 additional carbon atoms or a salt thereof,        and an activated derivative of the carboxyl terminated        derivative;

    -   i) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅,        wherein R¹ and R², together with the carbon atoms to which they        are bonded, comprises a ring where at least one hydrogen atom        thereof is optionally substituted with a halogen (e.g.,        fluorine, bromine, iodine);

    -   j) COCOH; or

    -   k) CH(CH₃)CO₂H or —OCOCH₃

R² is:

-   -   a) H, OH, COOH, or a halogen    -   b) C₁₋₆, carboxy or alkoxy group, or    -   c) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅,        wherein R¹ and R², together with the carbon atoms to which they        are bonded, comprises a ring where at least one hydrogen atom        thereof is optionally substituted with a halogen.

R³ is:

-   -   a) (W)_(m)—Y—(Z)_(n), wherein        -   W is a C₅₋₁₂ straight or branched (preferably 1S′CH₃, 2R′CH₃            dimethyl)alkyl (e.g., -pentyl, -hexyl, -heptyl, -octyl, or            -nonyl), alkenyl, alkynyl, group, or mixture thereof,            option-ally substituted with at least one halogen (e.g.,            halogen terminal group or even dihalogen),        -   Y is a bond, O, S, SO, SO₂, N(C₁₋₆ alkyl), or NCS,        -   Z is:            -   i) a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture                thereof, optionally substituted with at least one                halogen, optionally substituted with a terminal aromatic                ring,            -   ii) CN₁₋₃, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄                alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on                the amide nitrogen can be the same or different, or            -   iii) a phenyl or benzyl group, option-ally substituted                with halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, CN,                CF₃, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, or                CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on the amide                nitrogen can be the same or different, and wherein            -   m and n are the same or different, and each is either 0                or 1,    -   b) a C₅₋₁₂ alkyl or haloalkyl group, optionally substituted with        a terminal aromatic ring, CN₁₋₃NCS, CO₂H, or CO₂C₁₋₄ alkyl,        CONH₂, CONHC₁₋₄alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄        alkyl on the amide nitrogen can be the same or different, or    -   c) a C₅₋₁₂ alkene or alkyne group, option-ally substituted with        a halogen, dithiolene, terminal aromatic ring, CN₁₋₃, NCS, CO₂H,        or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂,        wherein each C₁₋₄ alkyl on the amide nitrogen can be the same or        different;

R⁴ is:

-   -   a) H or halogen (preferably bromine)    -   b) OH, or    -   c) C₁₋₆ alkoxyl or carboxyl;

R⁵ is:

-   -   a) H,    -   b) a C₁₋₄ alkyl group,    -   c) COOH,    -   d) OH, or OCH₃,    -   e) a O—C₁₋₅ alkyl (ether) or alkanoyl, optionally substituted        with at least one mono- or di-methylamino or ethylamino group,        or    -   f) a lactone; and

R⁶ is:

-   -   a) H or OH;    -   b) C₁₋₄ alkyl (preferably ethyl), alkenyl, alkynyl, group, or        mixture thereof,    -   c) O—C₁₋₄ alkyl, alkenyl, alkynyl, group, or mixture thereof, or    -   d) a prenyl, geranyl or farnesyl group, optionally substituted        at any position with one or more halogens,    -   e) (W)_(m), —Y—(Z)_(n), wherein        -   W is a C_(5-12 alkyl), alkenyl, alkynyl, group, or mixture            thereof, optionally substituted with at least one halogen,        -   Y is a bond, O, S, SO, SO₂, CO, NH, N(C₁₋₄ alkyl), or NCS,        -   Z is:            -   i) a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture                thereof, optionally substituted with at least one                halogen, optionally substituted with a terminal aromatic                ring,            -   ii) CN₁₋₃, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄alkyl,                or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on the                amide nitrogen can be the same or different, or            -   iii) a phenyl or benzyl group, optionally substituted                with halo, C₁₋₆, alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, CN,                CF₃, CO, H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC_(II) alkyl,                or CON(C₁₋₄alkyl)₂, wherein each C₁₋₄ alkyl on the amide                nitrogen can be the same or different, and wherein            -   m and n are the same or different, and each is either 0                or 1,    -   f) a C₅₋₁₂ alkyl or haloalkyl group, optionally substituted with        a terminal aromatic ring, CN, CH₂N₃, NCS, CO₂H, or CO₂C₁₋₄        alkyl, CONH₂, CONHC₁₋₄alkyl, or CON(C₁₋₄ alkyl)₂, wherein each        C₁₋₄ alkyl on the amide nitrogen can be the same or different,    -   g) a C₅₋₁₂ alkene or alkyne group, optionally substituted with a        halogen, dithiolene, terminal aromatic ring, CN, CH₂N₃, NCS,        CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄        alkyl)₂, wherein each C₁₋₄ alkyl on the amide nitrogen can be        the same or different, or    -   h) CH(CH₃) CO2H, CH₂OOOH, or —OCOCH₃.

Compounds according to Formula I preferably include a lactone, H, OH orOCH₃, —CH(CH₃) CO2H, or —OCOCH₃ as R¹ substituents. Preferredsubstituents at R² are hydrogen, halogen (most preferably fluorine)hydroxyl, COON, or methoxyl groups. Preferred substituents at R⁴ includeH or a halogen (most preferably bromine). Preferred substituents at R⁵include a lactone, H, OH, and OCH₃. Preferred substituents at R⁶ includeH, OH, ethyl, CH(CH₃)CO₂H, CH₂COOH, and —OCOCH₃. Where compounds offormula I are included, preferably R⁶ is methyl or ethyl. A morepreferred compound according to Formula I has hydroxyl substituents atR¹, R⁵, and a methyl substituent at R⁶; even more preferably, thecompound has a third hydroxyl substituent at R². Preferred substituentsat R³ are discussed elsewhere herein; however, the invention providescompounds according to Formula I, wherein R³ is:

-   -   a) (W)_(m)—Y—(Z)_(n), wherein        -   W is a C₅₋₁₂ alkyl, alkenyl, alkynyl (e.g., 2′-ynyl, 3′-ynyl            or 4′-ynyl), group, or mixture thereof, optionally            substituted with at least one halogen,        -   Y is a bond, O, S, SO, SO₂, CO, NH, N(C₁₋₆ alkyl), or NCS,        -   Z is:            -   i) a C₅₋₁₂ alkyl, alkenyl, alkynyl (e.g., 2′-ynyl,                3′-ynyl or 4′-ynyl), group, or mixture thereof,                optionally substituted with at least one halogen,                optionally substituted with a terminal aromatic ring,            -   ii) CN₁₋₃, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄                alkyl, or CON (C₁₋₄alkyl)₂, wherein each C₁₋₄ alkyl on                the amide nitrogen can be the same or different, or            -   iii) a phenyl or benzyl group, optionally substituted                with halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C alkylthio, CN,                CF₃, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, or                CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on the amide                nitrogen can be the same or different,            -   wherein at least one of W and Z includes a branched                chain and            -   wherein m and n are the same or different, and each is                either 0 or 1,    -   b) a terminally-branched, e.g., terminal dimethyl, C₅₋₁₂ alkyl        or haloalkyl group, optionally substituted with a terminal        aromatic ring, CN, CH₂N₃, NCS, CO₂H, or CO₂C₁₋₄alkyl, CONH₂,        CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄alkyl on        the amide nitrogen can be the same or different, or    -   c) a terminally-branched C₅₋₁₂ alkene or alkyne group,        optionally substituted with a halogen, dithiolane, terminal        aromatic ring, CN, CH₂N₃, NCS, CO₂H, or CO₂C₁₋₄alkyl, CONH₂,        CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on        the amide nitrogen can be the same or different.

Particularly preferred R³ substituents include C₅-C₁₂ alkynes, andparticularly preferred groups also include di- or tri-methyl terminalgroups. A most preferred substituent at R³ is a dimethylheptyl,particularly 1′S, 2′SR, and also preferably with terminal halogen (ordihalogen) substituents, and another preferred substituent is5,5-dimethyl Hex(1-en-3-ynyl) e.g., compound Many such compounds exhibitantineoplastic activity and can be employed as such, as describedherein. While any such compounds can be included within the compositionin accordance with the inventive method, some preferred compounds are asfollows:

As mentioned, compounds according to Formula I can have geranylsubstituents at R⁶. In this regard, at least one compound within thepharmacologically-acceptable composition can be cannabigerol or aderivative thereof having the following formula:

wherein:

R¹ is:

-   -   a) H,    -   b) a C₁₋₄ alkyl group or ester thereof,    -   c) COOH,    -   d) OH,    -   e) a O—C₁₋₅ alkyl (preferably OCH₃) or alkanoyl, optionally        substituted by mono- or dimethylamino or ethylamino groups,    -   f) a O—CO—C₃₋₁₀ alkyl group containing a carboxyl or amino        group,    -   g)

-   -   -   wherein n=1 to 8

    -   h) a p-aminobenzyl group or a C₁₋₇ aminoalkyl group or an        organic or mineral acid addition salt thereof, an isocyanate or        isothiocyanate derivative of the p-aminobenzyl or aminoalkyl        group, a carboxyl terminated derivative of the aminoalkyl group        having from 1 to 7 additional carbon atoms or a salt thereof,        and an activated derivative of the carboxyl terminated        derivative;

    -   i) R¹ and R² comprise a substituent of the formula —O(CH₂)₂₋₅,        wherein R¹ and R²,

    -   together with the carbon atoms to which they are bonded,        comprises a ring where at least one hydrogen atom thereof is        optionally substituted with a halogen (e.g., fluorine, chlorine,        bromine, iodine);

    -   j) COCOH; or

    -   k) CH(CH₃)CO₂H or —OCOCH₃

R² is:

-   -   a) H, OH, COOH, or a halogen    -   b) C₁₋₆, carboxy or alkoxy group, or    -   c) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅,        wherein R¹ and R², together with the carbon atoms to which they        are bonded, comprises a ring where at least one hydrogen atom        thereof is optionally substituted with a halogen.

R³ is:

-   -   a) (W)_(m)—Y—(Z)_(n), wherein        -   W is a C₅₋₁₂ straight or branched (preferably 1S′CH3, 2R′CH3            dimethyl) alkyl, alkenyl, alkynyl, group, or mixture            thereof, optionally substituted with at least one halogen,        -   Y is a bond, O, S, SO, SO₂, CO, NH, N(C₁₋₆ alkyl), or NCS,        -   Z is:            -   i) a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture                thereof, optionally substituted with at least one                halogen, optionally substituted with a terminal aromatic                ring,            -   ii) CN, CH2N3, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄                alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on                the amide nitrogen can be the same or different, or            -   iii) a phenyl or benzyl group, optionally substituted                with halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, CN,                CF₃, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, or                CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on the amide                nitrogen can be the same or different, and wherein            -   m and n are the same or different, and each is either 0                or 1,    -   b) a C₅₋₁₂ alkyl or haloalkyl group, optionally substituted with        a terminal aromatic ring, CN, CH₂N₃, NCS, CO₂H, or CO₂C₁₋₄        alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each        C₁₋₄ alkyl on the amide nitrogen can be the same or different,        or    -   c) a C₅₋₁₂ alkene or alkyne group, optionally substituted with a        halogen, dithiolane, terminal aromatic ring, CN, CH₂N₃, NCS,        CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄        alkyl)₂, wherein each C₁₋₄ alkyl on the amide nitrogen can be        the same or different;

R⁵ is:

-   -   a) H,    -   b) a C₁₋₄ alkyl group,    -   c) COOH,    -   d) OH, or OCH₃,    -   e) a O—C₁₋₅ alkyl (ether) or alkanoyl, optionally substituted        with at least one mono- or di-methylamino or ethylamino group,        or    -   f) a lactone; and

R⁶ is:

-   -   a) hydrogen,    -   b) C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl (preferably ethyl),        or C₁₋₆ haloalkyl,    -   c) CN,    -   d) CO₂H,    -   e) CO₂—C₁₋₄ alkyl,    -   f) C(Y)(Z)—OH,    -   g) C(Y)(Z)—O—C₁₋₄ alkyl, or C₁₋₆ alkyl-CO₂—Y    -   wherein Y and Z are each independently H or C₁₋₄ alkyl,

R⁷ is:

-   -   a) hydroxy (preferably (3-hydroxy) or lactone,    -   b) halo,    -   c) C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl, or C₁₋₆ haloalkyl,    -   d) CN,    -   e) N₃,    -   f) CO₂H,    -   g) CO₂C₁₋₄ alkyl,    -   h) C(Y)(Z)—OH,    -   i) C(Y) (Z)—O—C₁₋₄ alkyl,    -   j) C₁₋₆alkyl-CO₂—Y, or    -   k)═O or ═S,    -   wherein Y and Z are each independently H or C₁₋₆ alkyl, and        wherein R⁷ can be at any of positions 2-5.

Compounds according to Formulas I and II can be synthesized using knownprocedures from commercially available starting materials (see, e.g.,Dominianni et al., J. Org. Chem., 42, 344-46 (1977); Back et al., Arch.Pharm. Res., 19, 228-30 (1996); Guthrie et al., J. Org. Chem. 47,2369-76 (1982)). For example, acid catalyzed condensation of2,6-dimethoxyphenol with OH—R³ can produce a 4-alkylphenol intermediate.Conversion of the phenolic group to the diethylphosphate ester followedby reduction with lithium metal in liquid ammonia can then produce adimethoxybenzene derivative. Mono- or didemethylation of this compound(e.g., with boron tribromide) can then yield the desired methoxyphenoland/or resorcinol (Formula I), respectively. Compounds of Formula Ihaving alkyl substituents at R⁶ can be prepared, for example, first bylithiation of the dimethoxybenzene derivative at R⁶ (e.g., in thepresence of Bu/THF) and subsequent exposure to an alkylating agent(e.g., methyl or ethyl iodide or sulfate). Mono- or didemethylation ofthis compound (e.g., with boron tribromide) can then yield the desiredmethoxyphenol and/or resorcinol (Formula I), respectively, having thealkyl substituents at R⁶. Compounds of Formula II can be prepared, forexample, by acid catalyzed condensation of a methoxyphenol and/orresorcinol (Formula I) having a desired substituents at R³ with geraniol(e.g., in the presence of BF₃, Et₂O, silica, and CH₂Cl₂). Of course,these compounds can be synthesized by other appropriate methods, many ofwhich are known in the art.

In another embodiment at least one compound within the pharmacologicallyacceptable composition is a cannabinol derivative having the followingformula:

wherein,

R¹ is:

-   -   a) H,    -   b) a C₁₋₄ alkyl group or ester thereof,    -   c) COOH,    -   d) OH,    -   e) a O—C₁₋₅ alkyl (preferably OCH₃) or alkanoyl, optionally        substituted by mono- or dimethylamino or ethylamino groups,    -   f) a O—CO—C₃₋₁₀ alkyl group containing a carboxyl or amino        group,    -   g)

-   -   -   wherein n=1 to 8

    -   h) a p-aminobenzyl group or a C₁₋₇ aminoalkyl group or an        organic or mineral acid addition salt thereof, an isocyanate or        isothiocyanate derivative of the p-aminobenzyl or aminoalkyl        group, a carboxyl terminated derivative of the aminoalkyl group        having from 1 to 7 additional carbon atoms or a salt thereof and        an activated derivative of the carboxyl terminated derivative;

    -   i) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅,        wherein R¹ and R², together with the carbon atoms to which they        are bonded, comprises a ring where at least one hydrogen atom        thereof is optionally substituted with a halogen;

    -   j) COCOH; or

    -   k) CH(CH₃)CO₂H or —OCOCH₃

R² is:

-   -   a) H, OH, COOH, or a halogen    -   b) C₁₋₆ carboxy or alkoxy group, or    -   c) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅,        wherein R¹ and R², together with the carbon atoms to which they        are bonded, comprises a ring where at least one hydrogen atom        thereof is optionally substituted with a halogen

R³ is:

-   -   a) (W)_(m)—Y—(Z)_(n), wherein        -   W is a C₅₋₁₂ straight or branched (preferably 1S′CH₃, 2R′CH₃            dimethyl) alkyl, alkenyl, alkynyl, group, or mixture            thereof, optionally substituted with at least one halogen,        -   Y is a bond, O, S, SO, SO₂, CO, NH, N(C₁₋₆ alkyl) or NCS,        -   Z is:            -   i) a C₅₋₁₂ alkyl, alkenyl, alkynyl groups, or mixture                thereof, optionally substituted with at least one                halogen, optionally substituted with a terminal aromatic                ring,            -   ii) CN₁₋₃, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄                alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on                the amide nitrogen can be the same or different, or            -   iii) a phenyl or benzyl group, optionally substituted                with halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, CN,                CF₃, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, or                CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on the amide                nitrogen can be the same or different, and wherein            -   m and n are the same or different, and each is either 0                or 1,    -   b) a C₅₋₁₂ alkyl or haloalkyl group, optionally substituted with        a terminal aromatic ring, CN, CH₂N₃, NCS, CO₂H, or CO₂C₁₋₄        alkyl, CONH₂, CONHC₁₋₄alkyl, or CON(C₁₋₄ alkyl)₂, wherein each        C₁₋₄ alkyl on the amide nitrogen can be the same or different,        or    -   c) a C₅₋₁₂ alkene or alkyne group, optionally substituted with a        halogen, dithiolene, terminal aromatic ring, CN, CH₂N₃, NCS,        CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄        alkyl)₂, wherein each C₁₋₄ alkyl on the amide nitrogen can be        the same or different;

R⁶ and R⁶′ together form ═O or ═S, or each is independently selectedfrom the group consisting of:

-   -   a) hydrogen,    -   b) C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl, or C₁₋₆ haloalkyl,    -   c) CN,    -   d) CO₂H,    -   e) CO₂—C₁₋₄ alkyl,    -   f) C(Y)(Z)—OH,    -   g) C(Y)(Z)—O—C₁₋₄ alkyl, and    -   h) C₁₋₆ alkyl-CO₂Y,

wherein Y and Z are each independently H or C₁₋₆ alkyl,

R⁷ is

-   -   a) hydroxy or lactone,    -   b) halo,    -   C) C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl, or C₁₋₆ haloalkyl,    -   d) CN,    -   e) N₃,    -   f) CO₂H,    -   g) CO₂—C₁₋₄ alkyl,    -   h) C(Y)(Z)—OH,    -   i) C(Y)(Z)—C₁₋₄ alkyl,    -   j) C₁₋₆ alky-CO₂—Y, or    -   k) ═O or ═S,        wherein Y and Z are each independently H or C₁₋₆ alkyl;

Q is:

-   -   a) O or S, or    -   b) N—W,    -   wherein W is:    -   i) hydrogen,    -   ii) C₁₋₆ alkoxyalkyl, C₁₋₆ alkyl, or C₁₋₆ haloalkyl    -   iii) OC₁₋₆ alkyl, or OC₁₋₆ haloalkyl,    -   iv) CN,    -   v) C₁₋₆ alkyl,    -   vi) C(Y)(Z) C1⁻⁴ alkyl, or    -   vii) alkyl-CO₂—Z,        wherein Y and Z are each independently H or C₁₋₆ alkyl.

It is known in the art that some compounds according to Formula III arepsychoactive, chiefly via agonism of the CB1 receptor. Thus, in someapplications, it may be preferable to employ substituents within FormulaIII (e.g., of R¹-R⁷, Q, and ring C) that preferably promote CB2 agonistactivity, rather than CB1 activity, and are more preferably substituentsthat promote selective CB2 agonist activity. In some embodiments, tomitigate or eliminate psychoactive effects attributed to somecannabinoids, the inventive method employs a selective CB2 agonist,which is one that preferentially acts on the CB2 receptor, as opposed tothe CB1 receptor. Most preferably, the selective CB2 agonist does notbind the CB1 receptor at concentrations in which it activates the CB2receptor. Various selective CB2 agonists are known in the art. Examplesof such compounds include classical and nonclassical cannabinoids,bicyclic cannabinoids, aminoalkylindoles, and eicosanoids (see, e.g.,Pertwee, Pharmacol. Ther, 74(2), 129-80 (1997)). To assess whether agiven compound is a selective CB2 agonist, its relative affinity for theCB2 and CB1 receptors can be assessed using any suitable method, forexample using cells engineered to express the receptors (Ross et al., BrJ. Pharmacol., 126, 665-72 (1999)). Such values typically are expressedas a binding constant, K, from which a ratio of K/K_(i) _(—) _(CB2) canbe calculated. Desirably, the selective CB2 agonist has a K, for the CB2receptor of from about 100 nM to about 0.1 nM, preferably from about 25nM to about 0.2 nM, such as from about 15 nM to about 0.5 nM. Moreover,the ratio of K_(i-CB1)/K-_(CB2) is at least about 1.5, and morepreferably at least about 5 (e.g., at least about 10). Many compoundsare known to have suitable CB2 selectivity for use as a CB2 agonist inthe inventive method. For example, JWH-015 has a K_(i-CB2) of 13.8±4.6nM and a K_(i-CB1) K_(i-CB2) ratio of 27.5; WIN-55, 212-2 has aK_(i-CB2) of 0.028±0.16 nM and a K_(i-CB1)/K_(i-CB2) ratio of 6.75;5-F4B-THO has a K_(i-CB2) of 8.7.±3.5 nM and a K_(i-CB1)/K-_(CB2) ratioof 6.55; JWH-018 has a K_(i-CB2) of 2.94±2.65 nM and aK_(i-CB1)/K_(i-CB2) ratio of 3.23; CP-56,667 has a K_(1-CB2) of 23.6±6.5nM and a K_(i-CB1)/K_(i-CB2) ratio of 2.61; L759656 has a K_(i-CB2) of11.8±2.5 nM and a K_(i-CB1)/K_(i-CB2) ratio of 414.24; and L759633 has aK of 6.4±2.2 nM and a K_(i-CB1)/K_(i-CB2) ratio of 162.97 (seeabove-referenced references). It is within the ordinary skill in the artto assess these values for yet-unmeasured (or novel) compounds. Asidefrom binding the CB2 receptor preferentially, a preferred selective CB2agonist exhibits greater CB2-directed physiological response than CBIresponse. A classic assay for differential activity measures the abilityof a compound to inhibit drug-induced cyclic AMP (cAMP) production incells engineered to express the respective receptor, typically expressedas EC₅₀ (a percent-age of maximal effects) (Ross et al., Br J,Pharmacol., 126, 665-72 (1999)). Preferably, selective CB2 agonisttypically exhibits a EC_(50-CB2)/EC_(50-CB1) ratio of greater than about10, more typically greater than about 100 (e.g., greater than about500). Many compounds are known to have suitable CB2 selectivity, andthus can be used as a CB2 agonist in the inventive method. For example,L759656 has an EC_(50CB2)/EC_(50CB1) ratio of >3000; and L759633 has aEC_(50CB2)/EC_(50CB1) ratio of >1000. It is within the ordinary skill inthe art to assess these values for yet-unmeasured (or novel) compounds.

For CB2 selectivity, R¹ in Formula III preferably is not OH, as it is inthe natural cannabinol and tetrahydrocannabinol compounds. Rather,preferably R¹ in Formula III is. H, O—C₁₋₄alkyl (more preferablymethoxy) or a hemi ester of succinic acid, malonic acid or the alaninateester of alanine and salts thereof. In another preferred embodiment, R¹and R² together comprise a substituent of the formula —O(CH₂)₃₋₅,wherein R¹ and R², together with the carbon atoms to which they arebonded, comprise a ring where at least one hydrogen atom thereof isoptionally substituted with a halogen (e.g., an 0,2 propano ring).Furthermore, where R²Formula III is a halogen, preferably it is iodo.Preferably, R⁶ and R⁶′ together form ═O or each are methyl, ethyl, ormethoxy. While R⁷ can be at any of positions 7-10 of ring C, preferablyit is at position 9 of the ring. Where it is desired to promote CB2selectivity, R⁷ preferably is electronegative (e.g., COOH, halogen,13-hydroxy, or lactone.), and to enhance activity, it can be substitutedwith either a lactone or a hydroxy group.

Ring C in Formula III can be any of the following (the dashed linesrepresenting a double bond at Δ6a-10a, Δ8-9, or Δ9-10 position):

However, to promote CB2 selectivity, preferably the ring is aromatic. Inthis regard, a preferred embodiment of the invention provides novelanti-viral cannabinol derivatives according to Formula III, wherein ringC is aromatic. In such compounds, R⁷ preferably is electronegative andmore preferably is on C9. Furthermore, R¹ preferably is other than OHand preferably is deoxy, an ester, or ether. Exemplary cannabinolderivative compounds include:

Many compounds according to Formula III are well known, and others canbe manufactured in accordance with published methods (see, for example,International Patent Application W099/20268 (Burstein), and U.S. Pat.No. 2,509,386 (Adams), U.S. Pat. No. 3,799,946 (Loev), U.S. Pat. No.3,856,821 (Loev), U.S. Pat. No. 3,897,306 (Vidic et al.), U.S. Pat. No.4,064,009 (Fukada et al.), U.S. Pat. No. 4,087,545 (Archer et al.), U.S.Pat. No. 4,142,139 (Bindra), U.S. Pat. No. 4,309,545 (Johnson), U.S.Pat. No. 4,599,327 (Nogradi et al.), U.S. Pat. No. 4,833,073 (McNally etal.), U.S. Pat. No. 4,876,276 (Mechoulan et al.), U.S. Pat. No.4,973,603 (Burstein), U.S. Pat. No. 5,338,753 (Burstein et al.), U.S.Pat. No. 5,389,375 (ElSohly), U.S. Pat. No. 5,440,052 (Makriyannis etal.), U.S. Pat. No. 5,605,906 (Lau), and U.S. Pat. No. 5,635,530(Mechoulam et al.); and Charalambous et al., Pharm. Biochem. Behav., 40,509-12 (191), Gareau et al., Bioorg. Med. Chem. Lett., 6(2), 189-94(1996), Griffin et al., Br J. Pharmacol., 126, 1575-84 (1999), Huffmanet al., Bioorg. Med. Chem. Lett., 6, 2281-88 (1998), Lemberger et al.,Clin. Pharmacol. Ther, 18(6), 720-26 (1975), Loev et al., J. Med. Chem.,16(11), 1200-06 9 (1973), Loev et al., J. Med. Chem., 17(11), 1234-35(1974), Martin et al., Pharm. Biochem. Behav., 46, 295-301 (1993),Papahatjis et al., J. Med. Chem., 41](7), 1195-1200 (1998), Pars et al.,J. Med. Chem., 19(4), 445-53 (1976), Pertwee et al., Pharmacol. Ther,74(2), 129-80 (1997), Razdan et al., J. Med. Chem., 19(4), 454-60(1976), Razdan, Pharmacol. Reviews, 38(2) 75-149 (1980), Reggio et al.,J. Med. Chem., 40(20), 3312-18 (1997), Reggio et al., Life Sci.,56(23/24), 2025-32 (1995), (Ross et al., Br J. Pharmacol., 126, 665-72(1999), Thomas et al., J. Pharm. Exp. Ther, 285(1), 285-92 (1998), Wileyet al., J. Pharm. Exp. Ther, 285(1), 995-1004 (1998), Winn et al., J.Med. Chem., 19(4), 461-71 (1976), and Xie et al., J. Med. Chem., 41,167-74 (1998)).

In the preferred embodiment wherein ring C of Formula III is aromatic,such compounds additionally can be manufactured by aromatizing anappropriate tetrahydrocannabinol (THC) derivative molecule by knownmethods (see, e.g., Adams et al., J. Am. Chem. Soc., 62, 23401 (1940);Ghosh et al., J. Chem. Soc., 1393 (1940); and Adams et al., J. Am. Chem.Soc., 70, 664 (1948)). For example, aromatization of such compounds canoccur by heating the compound with sulfur at about 238-240° C., under anitrogen atmosphere; for about 4 hours (Rhee et al., J. Med. Chem.,40(20), 3228-33 (1997)). Other suitable methods include aromatizationusing a catalyst (e.g., palladium on carbon) or a chemicaldehydrogenating agent (e.g., 2,3-dichloro-5,6-dicyanoquinone) (see, forexample, U.S. Pat. No. 3,799,946 (Loev)).

As mentioned, in some applications of the inventive method, particularlywhere at least one of the compounds within the composition is acannabinol derivative, it is desirable to mitigate potentiallydeleterious psychoactivity attributed to some such compounds. As analternative to employing non-psychoactive cannabinol derivatives (e.g.,selective CB2 agonists) within the composition, otherpharmacologically-active agents can be employed in addition to mitigatepsychoactive effects. For example, as some of the aforementionedcompounds might exert some activity on CBI receptors, it is oftendesirable to adjunctively administer a selective CB1 antagonist to thepatient. Indeed, in some applications it is desired to co-administer anon-selective CB2 agonist (e.g., Δ8- or Δ9-THC and derivatives thereof)in small doses, in which cases administration of a CB1 antagonist ispreferred. Many suitable selective CBI antagonists are known in the art(Rinaldi-Carmona et al., FEBS Lett., 350, 240-44 (1994), see also U.S.Pat. No. 5,624,941 (Barth et al.), U.S. Pat. No. 5,747,524 (Cullinan etal.), U.S. Pat. No. 5,925,768 (Barth et al.)). SR-1241716A is aparticularly potent, and theretofore preferred, selective CBI antagonistfor use in the inventive method. Other preferred selective CBIantagonists are cannabidiol and its derivatives (see, e.g., U.S. Pat.No. 2,304,669 (Adams); Razdan et al., Pharmacol. Reviews, 38(2), 75-149(1986); Reggio et al., Life Sci., 56(23-24), 2025-32 (1995)), as thesepotently antagonize the CB1 receptor. In addition to antagonizing CB1,cannabidiol and many of its derivatives also advantageously attenuatethe cytochrome P_(45O) system in the liver, leading to enhancedbioavailability of other compounds within the composition (e.g.,Bornheim et al., Chem. Res. Toxicol., 11, 1209-16 (1998)). In thisregard, in some embodiments of the inventive method, at least onecompound within the pharmacologically-acceptable composition iscannabidiol or a derivative thereof having the following formula:

wherein:

R¹ is: a) H,

b) a C₁₋₄ alkyl group or ester thereof, c) COOH,

d) OH,

e) a O—C₁₋₅ alkyl (preferably OCH₃) or alkanoyl, optionally substitutedby mono- or di-methylamino or ethylamino groups,f) a O—CO—C₃₋₁₀ alkyl group containing a carboxyl or amino group,g)

-   -   wherein n=1 to 8        h) a p-aminobenzyl group or a C₁₋₇ aminoalkyl group or an        organic or mineral acid addition salt thereof, an isocyanate or        isothiocyanate derivative of the p-aminobenzyl or aminoalkyl        group, a carboxyl terminated derivative of the aminoalkyl group        having from 1 to 7 additional carbon atoms or a salt thereof,        and an activated derivative of the carboxyl terminated        derivative;        i) R¹ and R² comprise a substituent of the formula —O(CH₂)₂₋₅,        wherein R¹ and R², together with the carbon atoms to which they        are bonded, comprises a ring where at least one hydrogen atom        thereof is optionally substituted with a halogen (e.g.,        fluorine, chlorine, bromine, iodine);

j) COCOH; or k) CH(CH₃)CO₂H or —OCOCH₃ R² is:

a) H, OH, COOH, or a halogenb) C₁₋₆, carboxy or alkoxy group, orc) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅, whereinR¹ and R², together with the carbon atoms to which they are bonded,comprises a ring where at least one hydrogen atom thereof is optionallysubstituted with a halogen.

R³ is:

-   -   a) (W)_(m) —Y—(Z)_(n), wherein    -   W is a C₅₋₁₂ straight or branched (preferably 1S′CH₃, 2R′CH₃        dimethyl)alkyl, alkenyl, alkynyl, group, or mixture thereof,        optionally substituted with at least one halogen,    -   Y is a bond, O, S, SO, SO₂, N(C₁₋₆ alkyl), or NCS,    -   Z is:        -   i) a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture            thereof, optionally substituted with at least one halogen,            optionally substituted with a terminal aromatic ring,        -   ii) CN, CH₂N₃—CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl,            or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on the amide            nitrogen can be the same or different, or        -   iii) a phenyl or benzyl group, option-ally substituted with            halo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, CN, CF₃,            CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄            alkyl)₂, wherein each C₁₋₄ alkyl on the amide nitrogen can            be the same or different, and wherein

m and n are the same or different, and each is either 0 or 1,

-   -   b) a C₅₋₁₂ alkyl or haloalkyl group, optionally substituted with        a terminal aromatic ring, CN, CH₂N₃, NCS, CO₂H, or CO₂C₁₋₄        alkyl, CONH₂, CONHC₁₋₄alkyl, or CON(C₁₋₄ alkyl)₂, wherein each        C₁₋₄ alkyl on the amide nitrogen can be the same or different,        or    -   c) a C₅₋₁₂ alkene or alkyne group, option-ally substituted with        a halogen, dithiolene, terminal aromatic ring, CN₁₋₃, NCS, CO₂H,        or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂,        wherein each C₁₋₄ alkyl on the amide nitrogen can be the same or        different;

R⁵ is: a) H

b) a C₁₋₄ alkyl group

c) COOH d) OH, or

e) a O—C₁₋₅ alkyl (ether) or alkanoyl, optionally substituted with atleast one mono- or di-methylamino or ethylamino group;

R⁶ is:

-   -   a) hydrogen,    -   b) C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl, or C₁₋₆ haloalkyl    -   c) CN,    -   d) CO₂H,    -   e) CO₂C₁₋₄ alkyl,    -   f) C(Y)(Z)—OH    -   g) C(Y)(Z)—O—C₁₋₄ alkyl, or    -   h) C₁₋₆ alkyl-CO₂—Y,    -   wherein Y and Z are each independently H or C₁₋₆ alkyl,

R⁷ is:

a) hydroxy or lactone,b) halo,c) C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆-carboxy, or C₁₋₆ haloalkyl,

d) CN, e) N₃, f) CO₂H,

g) CO₂—C₁₋₄ alkyl,

h) C(Y)(Z)—OH,

i) C(Y)(Z)—O—C₁₋₄ alkyl,j) C₁₋₆alkyl-CO₂—Y, ork)═O or ═S,wherein Y and Z are each independently H or C₁₋₆ alkyl, and wherein R⁷can be at any of positions 1, 2, 5, or 6 of ring C.

Another preferred compound for use in the inventive method is acannabichromene derivative having the following formula:

wherein,

R¹ is:

-   -   a) H,    -   b) a C₁₋₄ alkyl group or ester thereof,    -   c) COOH,    -   d) OH,    -   e) a O—C₁₋₅ alkyl (preferably OCH₃) or alkanoyl, optionally        substituted by mono- or dimethylamino or ethylamino groups,    -   f) a O—CO—C₃₋₁₀ alkyl group containing a carboxyl or amino        group,    -   g)

-   -   -   wherein n=1 to 8

    -   h) a p-aminobenzyl group or a C₁₋₇ aminoalkyl group or an        organic or mineral acid addition salt thereof, an isocyanate or        isothiocyanate derivative of the p-aminobenzyl or aminoalkyl        group, a carboxyl terminated derivative of the aminoalkyl group        having from 1 to 7 additional carbon atoms or a salt thereof,        and an activated derivative of the carboxyl terminated        derivative;

    -   i) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅,        wherein R¹ and R², together with the carbon atoms to which they        are bonded, comprises a ring where at least one hydrogen atom        thereof is optionally substituted with a halogen (e.g.,        fluorine, chlorine, bromine, iodine, astatine);

    -   j) COCOH; or

    -   k) CH(CH₃)CO₂H or —OCOCH₃

R² is:

a) H, OH, COOH, or a halogenb) C₁₋₆ carboxy or alkoxy group, orc) R¹ and R² comprise a substituent of the formula —O(CH₂)₃₋₅, whereinR¹ and R², together with the carbon atoms to which they are bonded,comprises a ring where at least one hydrogen atom thereof is optionallysubstituted with a halogen.

R³ is:

a) (W)_(m) —Y—(Z)_(n), whereinW is a C₅₋₁₂ straight or branched (preferably 1 S′CH₃, 2R′CH₃ dimethyl)alkyl, alkenyl, alkynyl, group, or mixture thereof, optionallysubstituted with at least one halogen,Y is a bond, O, S, SO, SO₂, CO, NH, N(C₁₋₄ alkyl), or NCS,

Z is:

i) a C₅₋₁₂ alkyl, alkenyl, alkynyl, group, or mixture thereof,optionally substituted with at least one halogen, optionally substitutedwith a terminal aromatic ring,

ii) CN, CH₂N₃, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, orCON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on the amide nitrogen can bethe same or different, or

iii) a phenyl or benzyl group, optionally substituted with halo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, CN, CF₃, CO₂H, or CO₂C₁₋₄ alkyl,CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl onthe amide nitrogen can be the same or different, and wherein

m and n are the same or different, and each is either 0 or 1,

b) a C₅₋₁₂ alkyl or haloalkyl group, optionally substituted with aterminal aromatic ring, CN, CH₂N₃, NCS, CO₂H, or CO₂C₁₋₄ alkyl, CONH₂,CONHC₁₋₄alkyl, or CON(C₁₋₄ alkyl)₂, wherein each C₁₋₄ alkyl on the amidenitrogen can be the same or different, orc) a C₅₋₁₂ alkene or alkyne group, option-ally substituted with ahalogen, dithiolane, terminal aromatic ring, CN, CH₂N₃, NCS, CO₂H, orCO₂C₁₋₄ alkyl, CONH₂, CONHC₁₋₄ alkyl, or CON(C₁₋₄ alkyl)₂, wherein eachC₁₋₄ alkyl on the amide nitrogen can be the same or different;R⁶ is selected from the group consisting of:a) hydrogen,b) hydroxy or lactone,c) halo,d) C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl, or C₁₋₆ haloalkyl,

e) CN, f) N₃, g) CO₂H,

h) CO₂—C₁₋₄ alkyl,

i) C(Y)(Z)—OH,

j) C(Y)(Z)—O—C₁₋₄ alkyl, andk) C₁₋₆ alkyl-CO₂—Y,wherein Y and Z are each independently H or C₁₋₆ alkyl,R⁷ is selected from the group consisting of:a) hydrogen,b) hydroxy or lactone,c) halo,d) C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl, or C₁₋₆ haloalkyl,

e) CN, f) N₃, g) CO₂H,

h) CO₂—C₁₋₄ alkyl,

i) C(Y)(Z)—OH,

j) C(Y)(Z)—O—C₁₋₄alkylk) C₁₋₆ alkyl-CO₂—Y, andl)═O or ═S;wherein Y and Z are each independently H or C₁₋₆ alkyl,R⁶ and R⁶′ together form ═O or ═S, or each is independently selectedfrom the group consisting of:a) hydrogen,b) hydroxy or lactone,c) halo,d) C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkyl, or C₁₋₆ haloalkyl,

e) CN, f) N₃, g) CO₂H,

h) CO₂—C₁₋₄ alkyl,

i) C(Y)(Z)—OH,

j) C(Y)(Z)—O—C₁₋₄ alkyl, andk) C₁₋₆ alkyl-CO₂ Y,

wherein Y and Z are each independently H or C₁₋₆ alkyl,

Q is: a) O or S, or

b) N—W, wherein W is:

i) hydrogen,

ii) C₁₋₆ alkoxyalkyl, C₁₋₆ alkyl, or C₁₋₆ haloalkyl iii) OC₁₋₆ alkyl, orOC₁₋₆ haloalkyl,

iv) CN,

v) C₁₋₆ alkyl,

vi) C(Y)(Z)C₁₋₄ alkyl, or

vii) C₁₋₆ alkyl-CO₂—Z,

wherein Y and Z are each independently H or C₁₋₆ alkyl.

Many cannabichromene derivatives are known, and others can besynthesized using methods that are known in the art (see, e.g., U.S.Pat. No. 4,315,862).

In addition to having the indicated substituents, R³ in any of formulasI-V preferably is:

wherein W₁ is H, methyl, or ethyl, wherein W₂ and W₃ are eachindependently H or methyl, wherein at least one of W₁, W₂, and W₃ isother than H and/or halogenated, and wherein W₄ is a C₁₋₄ alkyl orhaloalkyl, optionally substituted with an aromatic ring. Preferably, R³is a branched C₆₋₂ alkyl group containing at least one double bond (morepreferably at position C₄-C₁₀), and preferably the chain has an oddnumber of carbon atoms. More preferably, R³ is terminally branched orcontains a terminal double bond, and the invention provides compoundsaccording to Formulas I-V having such substituents. More preferably, R³preferably is dimethylheptyl (DMH) (e.g., 1′,1′ DMH or 1′R,2′S DMH),dimethylhexyl, or dimethylpentyl. For example, R³ can be a di- tri- ortetramethylpentyl, -hexyl, or -heptyl, etc., chain (e.g.,1,1,5-trimethylhexyl, 1,1,5,5-tetramethylhexyl, or1,1,5-trimethyl-hept-4-enyl). In some instances, the R³ substituent canhave bulky terminal moieties, for example, methyl, dimethyl, (CH₂)₁₋₆CON(CH₃)₂, or C₆₋₁₂ haloalkyl with halogenated terminal carbon atoms(preferably bromine).

In the context of this invention, halogenated alkanes, alkenes, andalkynes can have any number of halogen substitutions. In a preferredembodiment, the halogenated alkane, alkene, or alkyne has at least onehalogen on a terminal carbon atom (e.g., CX₁₋₃, wherein X is halogen).Alkyl groups (as well as alkenes and alkynes) can be straight chain orbranched. Moreover, the compounds can exist as a single stereoisomer ora mixture of stereoisomers (e.g., a racemic mixture), or a singlegeometric isomer (e.g., E, Z, cis or trans) or a mixture of geometricisomers, all of which are within the scope of the invention.

In carrying out the inventive method, the composition can be deliveredto a patient in any amount and over any time course suitable forproducing the desired therapeutic effect, and one of skill in the artwill be able to determine an acceptable dosing schedule. For example,where the method is employed to treat HIV disease, an optimal dosage canbe assessed by assaying the number of circulating viral particles (viralload) and/or CD4+ cell count in response to increasing dosage.Typically, the composition is delivered to a patient between 1 and about6 times a day, if not continuously through transdermal or time releaseformulations. However, in some applications, it is appropriate toadminister the composition less often. Generally each dose is betweenabout 2 mg/m3 to about 1000 mg/m3, and more preferably about 0.01mg/kg/day, about 1 mg/kg/day, such as about 1 mg/kg/day to about 10mg/kg/day, and can be up to about 100 mg/kg/day (e.g., about 250mg/kg/day). These dosages can be somewhat reduced when the compositionis employed in combination with other agents, and especially when thecytochrome P₄₅₀ system is attenuated (e.g., through cannabidiolderivatives), as discussed herein. Moreover, where a selective CB1antagonist is employed, it can be administered in the same dose orcomposition as the inventive composition or in a different formulationor dosing schedule. In some applications, it is preferable to beginadministering the selective CB1 antagonist prior to (e.g., at least 1-4days prior to) the composition, to further minimize any residualactivation of the CB1 receptor and to prevent degradation of thecompound(s) within the composition. Of course, as some patients candevelop tolerance to one or more compounds within the composition overthe course of treatment, the dosage amount and/or schedule can beadjusted as appropriate. Moreover, the dosage amount and schedule can bereduced as a patient responds favorably to treatment and/or if any toxicside effects are noted.

By virtue of its many effects, the method can be employed to treat manydiseases or disorders associated with immune dysfunction in addition toHIV disease. For example, the method can treat autoimmune diseases(e.g., systemic lupus-erythrematosis, Hashimoto's thyroiditis, Grave'sdisease, myasthenia gravis, rheumatoid arthritis, multiple sclerosis,Guillan-Barre syndrome, glomerulonephritis, polyarteritis nodosa,psoriasis etc.). The method can also treat diseases causing or dependingon inflammatory conditions (e.g., Crohn's disease, ulcerative colitis,forms of asthma, cystic fibrosis, Alzheimer's disease, atherosclerosisand associated cardiovascular diseases), and it is particularlyeffective in combating many neoplastic diseases, microbial (e.g.,mycobacterial, fungal) infections, or viral infections, especially HSV,Epstein-Barr virus, Cytomegalovirus, HIV, and hepatitis B and C). Themethod can also treat abnormal immune responses, abnormal scar formation(e.g., surgical adhesions or keloids), allograft rejection,atherosclerosis and associated heart diseases. Of course, the patientcan be any sort of animal (e.g., a monkey, cat, dog, horse, cow, pigs,goat, and sheep, etc.).

Of course, where the method is employed to combat a disease associatedwith immune dysfunction, other appropriate therapeutic agents can beadjunctively employed as well. For example, the method can include theadjunctive administration of antineoplastics, antitumor agents,antibiotics, antifungals, antivirals (particularly antiretroviralcompounds), antihelminthic, and antiparasitic compounds. Exemplaryantiviral agents suitable for adjunctive use in the inventive methodinclude abacavir, azidothymidine cidofovir, delavirdine mesylate,didanosine, dideoxycytidine, efavirenz, foscarnet, ganciclovir,indinavir sulfate, lamivudine, nelfinavir mesylate, nevirapine,ritonavir, saquinavir, saquinavir mesylate, stavudine, zalcitabine, etc.In treating tumors or neoplastic growths, suitable adjunctive compoundscan include anthracycline antibiotics (such as doxombicin, daunorubicin,carinomycin, N-acetyl adri amycin, rubidazone, 5-imidodaunomycin, andN-acetyldaunomycin, and epirubicin) and plant alkaloids (such asvincristine, vinblastine, etoposide, ellipticine and camptothecin),paclitaxel and docetaxol, mitotane, cisplatin, phenesterine, etc.Anti-inflammatory therapeutic agents suitable for adjunctive use in thepresent invention include steroids and non-steroidal anti-inflammatorycompounds, (such as prednisone, methyl-prednisolone, paramethazone,11-fludrocortisol or fluorocortisone, triamciniolone, betamethasone anddexamethasone, ibuprofen, piroxicam, beclomethasone; methotrexate,azaribine, etretinate, anthralin, psoralins); salicylates (such asaspirin; and immunosuppresant agents such as cyclosporine). Additionalpharmacologic agents suitable for adjunctive use in the inventive methodinclude anesthetics (such as methoxyflurane, isoflurane, enflurane,halothane, and benzocaine); antiulceratives (such as cimetidine);antiseizure medications (such as barbituates; azothioprine (animmunosuppressant and antirheumatic agent); and muscle relaxants (suchas dantrolene and diazepam). Moreover, the method can be employed inconjunction with specific antibody therapies or steroid therapies intreating autoimmune diseases. Other pharmacologically-active agents thatcan be adjunctively employed in conjunction with the composition includeother constituents of natural marijuana having antimicrobial oranti-inflammatory activities (e.g., cannabigerol and its derivatives,cannabichromine and its derivatives, cannabinolic acid and itsderivatives, cannabidiolic acid and its derivatives, terpenoids,flavanoids (e.g., canniflavin), etc.).

The composition can include biologically active agents, such aslymphokines or cytokines, anti-inflammatory, anti-bacterial, anti-viral,anti-fungal, anti-parasitic, anti-metabolic, anti-inflammatory,vasoactive, anti-neoplastic, bronchoacting, local anesthetic,immunomodulating, enzymatic, hormonal, growth promoting and regeneratingagents, as well as neurotransmitters, and cell receptor proteins andligands, among many other agents. Examples of other biological agentsare analgesics (such as acetominophen, anilerdine, aspirin,buprenorphine, butabital, butorphanol, choline salicylate, codeine,dezocine, diclofenac, diflunisal, dihydrocodeine, elcatonin, etodolac,fenoprofen, hydrocodone, hydromorphone, ibuprofen, ketoprofen,ketorolac, levorphanol, magnesium salicylate, meclofenamate, mefenamicacid, meperidine, methadone, methotrimeprazine, morphine, nalbuphine,naproxen, opium, oxycodone, oxymorphone, pentazocine, phenobarbital,propoxyphene, salsalate, sodium salicylate, tramadol and narcoticanalgesics in addition to those listed above). Anti-anxiety agents arealso useful including alprazolam, bromazepam, buspirone,chlordiazepoxide, chlormezanone, clorazepate, diazepam, halazepam,hydroxyzine, ketaszolam, lorazepam, meprobamate, oxazepam and prazepam,among others. Other biologically-active agents include anti-anxietyagents associated with mental depression, such as chlordiazepoxide,amitriptyline, loxapine, maprotiline, and perphenazine, among others.Examples of other active ingredients include anti-inflammatory agentssuch as non-rheumatic aspirin, choline salicylate, diclofenac,diflunisal, etodolac, fenoprofen, floctafeninc, flurbiprofen, ibuprofen,indomethacin, ketoprofen, lidomide, magnesium salicylate, meclofenamate,mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone,piroxicam, salsalate, sodium salicylate, sulindac, tenoxicam,tiaprofenic acid, thalidomide, linomide, and tolmetin, as well asanti-inflammatories for ocular treatment (such as diclofenac,flurbiprofen, indomethacin, ketorolac, and rimexolone (generally forpost-operative treatment)), and anti-inflammatories for non-infectiousnasal applications (such as beclomethaxone, budesonide, dexamethasone,flunisolide, triamcinolone, and the like); soporifics(anti-insomnia/sleep inducing agents) such as those utilized fortreatment of insomnia, including alprazolam, bromazepam, diazepam,diphenhydramine, doxylamine, estazolam, flurazepam, halazepam,ketazolam, lorazepam, nitrazepam, prazepam quazepam, temazepam,triazolam, zolpidem and sopiclone, among others; sedatives includingdiphenhydramine, hydroxyzine, methotrimeprazine, promethazine, propofol,melatonin, trimeprazine, and the like; sedatives and agents used fortreatment of petit mal, seizures and tremors, among other conditions,such as amitriptyline HCl; chlordiazepoxide, amobarbital; secobarbital,aprobarbital, butabarbital, ethchlorvynol, glutethimide, L-tryptophan,mephobarbital, methohexital sodium salt, midazolam HCl, oxazepam,pentobarbital Na, Phenobarbital, secobarbital sodium salt, thiamylalsodium, and many others. Other active compounds can include agents usedin the treatment of head trauma (brain injury/ischemia), such asenadoline HCl (e.g., for treatment of severe head injury),cytoprotective agents, and agents for the treatment of menopause,menopausal symptoms (treatment), e.g., ergotamine, belladonna alkaloidsand phenobarbital, for the treatment of menopausal vasomotor symptoms,e.g., clonidine, conjugated estrogens and medroxyprogesterone,estradiol, estradiol cypionate, estradiol valerate, estrogens,conjugated estrogens, esterified estrone, estropipate, and ethinylestradiol. Examples of agents for treatment of pre menstrual syndrome(PMS) are progesterone, progestin, gonadotrophic releasing hormone, oralcontraceptives, danazol, luprolide acetate, vitamin B6; agents fortreatment of emotional/psychiatric treatments such as tricyclicantidepressants including amitriptyline hydrochloride (Elavil),perphenazine (Triavil) and doxepin HCl (Sinequan). Examples oftranquilizers, anti-depressants and anti-anxiety agents are diazepam(Valium), lorazepam (Ativan), alprazolam (Xanax), SSRI's (selectiveSeratonin reuptake inhibitors), fluoxetine hydrochloride (Prozac),sertraline hydrochloride (Zoloft), paroxetine hydrochloride (Paxil),fluvoxamine maleate (Luvox) venlafaxine hydrochloride (Effexor),serotonin, serotonin agonists (Fenfluramine); anti-biotics (e.g.,fluoroquinolones and tetracycline); antihistamines catabolic steroids;and vasoactive agents (e.g., betablockers and pentoxiphylline(Trental)). Other compounds include cannabinoids such as CT-3 andHU-210.

As mentioned, for use in the inventive method, the compound(s) areincorporated into a pharmacologically-acceptable composition including asuitable carrier, and optionally other inactive or active ingredients.Such compositions are suitable for delivery by a variety ofcommonly-employed routes of delivery, such as, for example, buccal,sublingual, dermal, intraocular, intraotical, pulmonary, transdermal,intralymphatic, intratumor, intracavitary, intranasal, subcutaneous,implantable, inhalable, intradermal, rectal, 1, transmucosal,intramuscular, intravenous and intraarticular routes, among many others.Depending on the desired manner of application, the composition caninclude adjuvants, bile salts, biodegradable polymers and co-polymers,buffers, chelating agents, colorants, diluents, emollients, emulsifiers,enzyme inhibitors, hydrogels, hydrophilic agents, lipoproteins and otherfatty acid derivatives, liposomes and other micelles, microporousmembranes, mucoadhesives, neutral and hydrophobic polymers andco-polymers, particulate systems, perfumes, salt forming acids andbases, semi-permeable membranes, single or multiple enteric coatings,solvents (e.g., alcohols, dimethyl sulfoxide (DMSO), etc.), surfactants,viral envelope proteins, or other ingredients.

In one of its forms, the composition can be an inhalable formulationcomprising an aerosol of liquid or solid particles, such as are known inthe art. Application of the composition via inhalation can treatbronchial conditions associated with inflammation (e.g., the common cold(rhinovirus), influenza, cystic fibrosis, etc.). This formulation canfurther comprise additional agents such as preservatives, antioxidants,flavoring agents, volatile oils, buffering agents, dispersants,surfactants, and the like, as are known in the art. Such formulation canalso be provided with an inhalant, or in the inhalant, either in unitform or in a form which permits its repetitive use.

The composition can also be a topical formulation (e.g., ointment,cream, lotion, paste, gel, spray, aerosol oil, etc.), wherein thecarrier is a diluent for the agent suitable for topical delivery, e.g.,petrolatum, lanoline, polyethylene glycols, alcohols and the like,optionally including trans-dermal enhancers. In the topical formulation,the carrier may be in a form suitable for formulating creams, gels,ointments, sprays, aerosols, patches, solutions, suspensions andemulsions.

The composition can also be formulated for oral delivery, for example inthe form of capsules, cachets, lozenges, tablets, powder, granules,solutions, suspensions, emulsions, essential oils (particularly hempseed oil), etc. Such formulations typically include aqueous ornon-aqueous liquid solutions and suspensions (e.g., oil-in-water orwater-in-oil emulsions). Such oral formulations typically are encased inan enteric coating. Examples of oral formulations are buccal orsub-lingual formulation comprising lozenges which can also compriseflavoring agents and other known ingredients, or pastilles which canalso comprise an inert base containing, for example, gelatin, glycerin,sucrose, acacia, and other ingredients and fillers as is known to thepractitioner.

The composition can also be a parenteral formulation, such as injectablesolutions and suspensions. Typically, such formulations also compriseagents such as anti-oxidants, buffers, anti-bacterial agents, otheranti-viral agents such as direct acting inhibitors of replication, andsolutes which render the solution or suspension isotonic with the bloodof an intended recipient. The solutions or suspensions are typicallysterile aqueous or non-aqueous injectable solutions or suspensions, andcan also comprise suspending agents and thickening agents. Thisformulation is generally provided in a sealed ampule or vial.

The composition can also be a slow release formulation, which, whenadministered or applied to a subject, is capable of releasing a desiredamount of the compound(s) over a pre-determined period of time.Alternatively, the composition can be a transdermal formulation, inwhich the carrier is suitable for facilitating the transdermal deliveryof the agent. Examples are aqueous and alcoholic solutions, DMSO, oilysolutions and suspensions, and oil-in-water or water-in-oil emulsions. Atransdermal formulation can also be an iontophoretic transdermalformulation, in which typically the carrier can be an aqueous and/oralcoholic solution, an oily solution or suspension and an oil-in-waterand water-in-oil emulsion. This formulation can further comprise atransdermal transport promoting agent, and be provided in the form of akit with a transdermal delivery device, preferably an iontophoreticdelivery device, many variations of which are known in the art.

Additional formulations of the composition include, but are not limitedto an implantable capsule or cartridge (e.g., for tissue implantation),a patch, an implant, or a suppository (e.g., for rectal or transmucosaladministration).

Typically, the composition will be distributed, either to physicians orto patients, in an administration kit, and the invention provides suchan immunomodulating kit. Typically, such kits include, in separatecontainers, an administration device (e.g., syringes and needles,inhalators, pills, suppositories, transdermal delivery devices, etc) anda plurality of unit dosages of the composition as described above. Insome kits, the composition can be preformulated. Other kits includeseparate ingredients for formulating the composition. The kit canadditionally comprise a carrier or diluent, a case, and instructions forformulating the composition (if applicable) and for employing theappropriate administration device.

As mentioned, compounds according to Formula I have antineoplastic orcytotoxic activity, and the invention provides a method of inhibitingthe growth of a neoplasm (e.g., a neoplastic cell or tumor), comprisingdelivering such a compound to the neoplasm under conditions sufficientfor the growth of the neoplasm to be inhibited. Without being bound byany particular theory, resorcinols as described herein can cause DNAcleavage, which can potentially induce apoptosis within neoplasticcells. In this regard, preferably the resorcinol derivative is deliveredto the neoplasm under conditions sufficient to potentiate apoptosis. Theexact dosing schedule needed to induce apoptosis will depend on the typeof compound employed, and whether additional compounds are alsoemployed. In this regard, the method can be delivered adjunctively, inconjunction with the delivery of at least one other antineoplastic agent(such as those set forth above).

In many applications, the method is employed in vivo (e.g., within apatient), such as within a tumor or blood dyscrasia. In some such invivo applications, the resorcinol derivative is delivered to theneoplasm by introducing it into systemic circulation, such as throughthe gastric, intestinal, oral, or rectal wall or via intravenousinjection. In still other applications where the neoplasm is orcomprises a tumor, the resorcinol derivative can be delivered byintratumoral injection. Such mode of delivery can, in some instances,increase the potential local concentration of the compound. For such invivo applications, the compound can be formulated into apharmacologically-acceptable composition as indicated herein, asappropriate.

The method can be employed to combat tumor growth, which, whilepreferable, need not result in elimination of the tumor or decrease intumor mass. In this regard, the method can be employed to attenuatetumor growth. Such an effect can, for example, make otherwise resistantneoplastic cells more susceptible to other antineoplastic agents, andthe method contemplates the adjunctive use of such other compounds, manyof which are known in the art (e.g., aldesleukin, altretamine,amifostine, asparaginase, azathioprine, bicalutamide, bicalutamide,bleomycin, busulfan, capecitabine, carboplatin, carmustine,chlorambucil, cisplatin injection, cladribine, cyclophosphamide,cyclosporine o, cytarabine, cytarabine liposome injection, dacarbazine,dactinomycin, daunorubicin, denileukin diftitox, dexrazoxane, docetaxel,doxorubicin, doxorubicin hydro-chloride, estramustine phosphate sodium,etoposide, etoposide phosphate, floxuridine pegaspargase, fludarabinephosphate, flutamide, gemcitabine HCl, goserelin, granisetronhydrochloride, hydroxyurca, idarubicin hydrochloride, ifosfamide,interferon alfa-2a, recombinant, interferon alfa-2b, irinotecanhydrochloride, leucovorin, leuprolide acetate, levamisole, lomustine,L-PAM, L-phenylalanine mustard, mechlorethamine, melphalan,mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantronehydrochloride, nilutamide, nilutamide, octreotide, ondansetronhydrochloride, paclitaxel, pamidronate disodium, pentostatin,phenylalanine mustard, plicamycin, polifeprosan 20 with carmustineimplant, porfimer sodium, procarbazine HCl, rituximab, sargrarnostim,streptozocin 2-deoxy-2-[[(methylnitrosoamino), tamoxifen citrate,teniposide, testolactone, thioguanine, thiotepa for injection, topotecanhydrochloride, toremifene citrate, trastuzumab, tretinoin, trimetrexateglucuronate, valrubicin, vinblastine sulfate, vincristine sulfate,vinorelbine tartrate, etc.). Moreover, even where tumor growthcontinues, such attenuation is useful for slowing the progress of thedisease, thus permitting greater time for other therapeutic approaches.Indeed, combination therapy may allow for smaller or greater doses ofother such antineoplastic agents for shorter or longer durations, thuspotentially facilitating increased efficacy and potentially reducingside effects.

EXAMPLES

While one of skilled in the art is fully able to practice the instantinvention upon reading the foregoing detailed description, the followingexamples will help elucidate some of its features. Of course, as theseexamples are presented for purely illustrative purposes, they should notbe used to construe the scope of the invention in a limited manner, butrather should be seen as expanding upon the foregoing description of theinvention as a whole.

Example 1

This example demonstrates the synthesis of a compound according toFormula I. A mixture of 2,6-dimethoxyphenol (73.4 g, 0.48 mole),2,6-dimethyl-2-heptanol (69.0 g, 0.48 mole) and methanesulfonic acid (95mL) was stirred at 50° C. for 3 h and then at room temperatureovernight. The mixture was poured over ice-water (600 mL) with stirring.The mixture was extracted with CH₂Cl₂ (2×200 mL). The extracts werewashed with water, saturated aqueous NaHCO₃, saturated aqueous sodiumchloride solution and dried over anhydrous Na₂SO₄. The solution wasconcentrated under reduced pressure to obtain the product as an oil (130g, 96%). Analysis of this substance (MS (NAB) m/z 281 (MH)′; ³H NMR(CDCl₃) δ0.80 (d, 6H), 1.0-1.1 (m, 4H), 1.27 (s, 6H), 1.40-1.60 (m, 3H),3.89 (s, 6H), 5.36 (s, 1H), 6.54 (s, 2H)) revealed it to be4-(1,1,5-trimethylhexyl)-2,6-dimethoxy phenol:

Example 2

This example demonstrates the synthesis of a compound according toFormula I. A solution of crude 4-(1,1,5-trimethylhexyl)-4,6,dimethoxyphenol from Example 1 (130 g, 0.46 mole) in dry CCl₄ (100 mL)was cooled in ice-bath and diethyl phosphite (70 mL, 0.54 mole) wasadded. To the stirred mixture triethylamine (75 mL, 0.54 mole) was addeddrop-wise at such a rate as to maintain the temperature of the reactionmixture below 10° C. The reaction mixture was stirred in the ice-bathfor 2 h and at room temperature overnight. The mixture was then dilutedwith CH₂Cl₂ (200 mL), washed with water, 4N aqueous NaOH (100 mL), 1Naqueous HCl (125 mL), water and saturated aqueous sodium chloridesolution. The extracts were dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by chromatographyover a column of silica using cyclohexane:EtOAc (7:1 to 3:1 gradient) asthe eluent to obtain 103 g (54%) of the product as a colorless waxy oil.Analysis of this substance (MS (FAB) m/z 417 (MH)′. ³H NMR (CDCl₃) δ0.81(d, 6H), 1.0-1.1 (m, 4H), 1.26 (s, 6H), 1.35-1.6 (m, 9H), 3.86 (s, 6H),4.25-4.38 (m, 4H), 6.53 (s, 2H)) revealed it to be4-(1,1,5-trimethylhexyl)-2,6-dimethoxyphenyl diethyl phosphate:

Example 3

This example demonstrates the synthesis of a compound according toFormula I. A solution of 4-(1,1,5-trimethylhexyl)-2,6-dimethoxyphenyldiethyl phosphate from Example 2 (82 g, 0.197 mole) in Et₂O (175 mL) andTHE (35 mL) was added slowly to liquid ammonia (450 mL) contained in a3-neck vessel fitted with mechanical stirrer, thermometer, dry icecondenser and a pressure equalizing addition funnel while adding smallfreshly cut pieces of lithium wire (2.8 g, 0.40 g-atom) at such a rateas to maintain a blue color. The reaction mixture was stirred furtherfor an hour and then quenched by the addition of saturated aqueous NH₄Cl(22 mL). Ether (220 mL) was added and the ammonia was allowed toevaporate overnight. The residue was treated with water (220 mL). Thelayers were separated and the ether layer was washed with 4N NaOH (200mL), water (2×200 mL) and saturated aqueous sodium chloride solution.The organic extracts were dried (MgSO₄) and concentrated under reducedpressure. The crude product was purified by chromatography over a columnof silica using cyclohexane:EtOAc (95:5) as the eluent to obtain 43 g(83%) of the product as a colorless oil. Analysis of this substance (MS(FAB) m/z 265 (MH)′; ³H NMR (CDCl₃) δ0.80 (d, 6H), 1.00-1.10 (m, 4H),1.26 (s, 6H), 1.4-1.6 (m, 3H), 3.79 (s, 6H), 6.30 (m, 1H), 6.49 (m, 2H))revealed it to be 4-(1,1,5-trimethylhexyl)-2,6-dimethoxybenzene:

Example 4

This example demonstrates the synthesis of a compound according toFormula I. A solution of 4-(1,1,5-trimethylhexyl)-2,6-dimethoxybenzenefrom Example 3 (10 g, 0.038 mole) in anhydrous CH₂Cl₂ (100 mL) wascooled in ice-bath and was treated dropwise with a solution of borontribromide in CH₂Cl₂ (100 mL of 1M solution, 0.10 mole) over a period of1 h. The mixture was stirred in the cold bath for 2 h and, then at roomtemperature overnight. The reaction mixture was cooled in ice-bath andcautiously treated with water (100 mL). The resulting mixture wasdiluted with CH₂Cl₂ (100 mL) and treated with half-saturated aqueoussodium bicarbonate solution. The layers were separated, the organiclayer was concentrated to half volume under reduced pressure andextracted with 2N aqueous NaOH (2×75 mL). The aqueous alkaline extractwas cooled and acidified to pH 3.0 with 1N aqueous HCl. The acidifiedmixture was extracted with Et₂O (2×100 mL). The ether layer was washedwith saturated aqueous sodium chloride solution, dried over anhydrousMgSO₄ and concentrated under reduced pressure. The crude product thusobtained was purified by chromatography over a column of silica usingcyclohexane:EtOAc (8:1 to 4:1 gradient) as the eluent to obtain 8.0 g(90%) of the product as colorless crystalline solid. Analysis of thissubstance (Mp 95-96° C. MS (FAB) m/z 237 (MH)′; ¹H NMR (CDCl₃) δ0.80 (d,6H), 1.00-1.10 (m, 4H), 1.23 (s, 6H), 1.40-1.58 (m, 3H), 4.65 (s, 2H),6.17 (m, 1H), 6.38 (m, 2H)) revealed it to be 4-(1,1,5-trimethylhexyl)resorcinol:

Example 5

This example demonstrates the synthesis of a compound according toFormula I. A solution of 4-(1,1,5-trimethylhexyl) resorcinol fromExample 4 (2 g, 0.0076 mole) in anhydrous CH₂Cl₂ (10 mL) was cooled inice-bath and was treated dropwise with a solution of boron tribromide inCH₂Cl₂ (2.6 mL of 1M solution, 0.0026 mole). The mixture was stirred inthe cold bath for 2 h and then at room temperature overnight. Themixture was cooled in ice-bath and cautiously treated with water (10 mL)followed by saturated aqueous sodium bicarbonate (5 mL). The organiclayer was separated, dried over MgSO₄ and concentrated under reducedpressure. The residue was purified by chromatography over a column ofsilica using cyclohexane:EtOAc (8:1 to 4:1 gradient) as the eluent toobtain 0.364 g (19%) of the product as a colorless oil. Analysis of thissubstance (MS (FAB) m/z 251 (MH)′; ¹H NMR (CDCl₃) δ 0.80 (d, 6H),1.00-1.10 (m, 4H), 1.24 (s, 6H), 1.4-1.6 (m, 3H), 3.78 (s, 3H), 4.67 (s,1H), 6.23 (m, 1H), 6.40 (m, 1H), 6.47 (m, 1H)) revealed it to be3-methoxy-5-(1,1,5-trimethylhexyl)phenol

Example 6

This example demonstrates the antiviral activity of several compoundsaccording to the invention.

Compounds. Compounds indicated in the table of FIG. 1 were prepared asvarying concentrations in SDMSA and used fresh.

Latently Infected Cells. 5×10³ Ul cells (obtained from the AIDS Researchand Reference Reagent Program, Bethesda, Md.) were plated in 96-wellplates with media with or without 5 ng/ml TNFa and a test compound.After 3 to 6 days incubation, the supernatants and cells were assessed

PBMC Isolation and Blasting. Peripheral blood mononuclear cells (PBMC)obtained from healthy HIV- and hepatitis-negative patients were washedto remove residual gradient separation material. The washed cells werethen counted, and their viability assessed. Following this initialpreparation, the cells are suspended in RPMI 1640 medium supplementedwith 15% inactivated fetal bovine serum, 2 mM L-glutamine, 100 U/mlpenicillin, 100 μg/ml streptomycin, and 10 μg/ml gentamycin with 2 μg/mlPHA at 1×10⁶ cells/ml. Following a 2 to 3 day incubation (37° C., 5%CO₂), the cells were collected by centrifugation, washed, andresuspended in the same medium, supplemented with recombinant IL-2. Thecultures were then maintained until use by ½ volume change with freshIL-12 containing medium every 3 days.

PBMC Assay. When ready for use, PBMCs from a minimum of two donors thathave been blasted with PHA and IL-1 were mixed, counted, and viabilitydetermined by trypan blue exclusion. The cells were then resuspended in1×10 cells/ml in RPMI 1640 supplemented with 15% fetal bovine serum(heat inactivated), 2 mM L-glutamine, 100 U/ml penicillin, 100 mg/mlstreptomycin, 10 μg/ml gentamycin and IL-2 (20 U/ml). 50 μl of cellswere then distributed to the inner 60 wells of a 96 well plate. Eachplate contains cell control wells (cells only), virus control wells(cells plus virus), drug toxicity control wells (cells plus testcompound), drug colorimetric control wells (drug only) as well asexperimental wells (drug plus cells plus virus). Diluted compounds werethen added to the microliter plate followed by the appropriatepre-titered strain of HIV-1. All samples were assayed in triplicate witha sister plate for the determination of compound toxicity. The finalvolume per well was 200 μl. The assay was incubated for 7 days at 37°C., 5% CO₂, after which supernatants were collected for analysis of RTactivity and sister plates for assessment of cell viability.

Monocyte Isolation and Culture. Peripheral blood monocytes (PBM) wereobtained from healthy HIV- and hepatitis-negative donors by ficollhypaque purification (optionally using recombinant IFNγ. After 7 days,the cultures were washed to remove non adherent cells, and testcompounds were added followed by HIV-1. Cultures were washed a finaltime by media removal 24 hours post infection, fresh test compound wasadded, and the cultures continued for an additional seven days. Virusreplication was then measured by expression of supernatant p24 antigenby commercially available ELISA assays. AZT was used as a positivecontrol run in parallel with each determination.

XTT Staining for Viability. Absence of toxicity was assessed byreduction of2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]2H-tetrazoliumhydroxide (XXT). 50 μl of a solution containing 1 mg/ml XTT and 0.06μg/ml phenazine methanesulfate (PMS) was added per well, and the platewas incubated for 4 hours at 37° C. Adhesive plate sealers were used inplace of the lids so that the sealed plates could be inverted severaltimes to mix the soluble reaction product. Following this incubation,the plates were read spectrophotometrically at 450 nm to assess thedegree of reduction product.

Analysis of p24. Viral protein production (p24) was assessed by standardELISA.Reverse Transcriptase Assay. HIV reverse transcriptase wasmeasured in cell free supernatants. Titrated TTP was resuspended indistilled H₂O at 5 Ci/ml. Poly rA and oligo dT were prepared as a stocksolution which was kept at −20° C. The RT reaction buffer (125 μl 1MEGTA, 125 μl dH₂O, 110 μl 10% SDS, 50 μl 1M Tris (pH 7.4), 50 μl 1M DTT,and 40 Ml 1M MgCl₂) was prepared fresh. The three solutions were thenmixed together in a ratio of 2 parts TTP, 1 part PolyrA: oligo dT, and 1part buffer. Ten μl of this reaction mixture was then placed in a roundbottom micro-liter plate, and 15 μl of virus-containing supernatant wasadded. The plate was incubated at 37° C. in a water bath with a solidsupport for 60 minutes. Following the reaction, the volume was spottedonto pieces of DE81 paper, washed 5 times for 5 minutes each in a 5%sodium phosphate buffer, 2 times for 1 minute in distilled water, 2times for 1 minute each in 70% ethanol, and then dried. Opti-Fluoro wasthen added to each sample and incorporated radioactivity was quantifiedusing a scintillation counter.

Data Analysis. IC₅₀ (i.e., 50% inhibition of virus replication), TC₅₀(50% cytotoxicity), and a selectivity index (SI═IC₅₀//TC₅₀) werecalculated for each assay. Pooled data for all compounds tested arepresented in FIG. 1. The results indicate that11-nor-A9-tetrahydrocannabidinol-9-carboxylic acid, cannabidiol, andolivitol, 5-(1,1,5-trimethylhexyl)resorcinol, and5-(1,1,5-trimethylhexyl)-2,6-dimethoxyphenol exhibited moderateantiviral activity. The antiviral activity of olivitol was morepronounced in the PBMCs and TNFa induced Ul cells than inmonocytes/macrophages or uninduced Ul cells. Particularly with referenceto the cannabinoids, these results are surprising, given observationsthat some such compounds can enhance, rather than suppress HIVreplication (see, e.g., Noe et al., Chapter 25 in Drug of Abuse,Immunomodullation and AIDS, Friedman et al., Ed., (Plenum Press, NY1998)).

Example 7

This example demonstrates the antineoplastic activity of compoundsaccording to Formula 1.

Cell Lines. Cell lines indicated in the table of FIG. 2 were propagatedunder sterile conditions in RPMI 1640 or DMEM with 10% fetal calf serum,2 mM L-glutamine, and sodium bicarbonate (“complete medium”) andincubated at 37° C. 5% CO₂ and 95% humidity. Each cell line wassubcultured once or twice weekly, and they were periodically screenedfor mycoplasma contamination (positive cultures were cured over threepassages with antibiotic). Only cultures free of mycoplasma were usedfor antineoplastic assessment.

Antineoplastic Assessment. Cells from each cell line were harvested,pelleted to remove the media, and then suspended in fresh completemedium. The cell count was determined and viability was measured withpropidium iodide staining. The cells were adjusted with complete mediumto a density of 5×10³ cells/ml. Tissue culture plates were seeded with100 μl samples of each cell line, and the plates were incubatedovernight to allow for cell anchorage and acclimation.

Following acclimation, the compounds indicated in FIG. 2 were diluted incomplete medium. A range of eight concentrations was used to treat thecell cultures. For each dilution, eight wells are each treated with 100μl of dosing solution. Each culture plate contains a cell control (8wells, mock treated with complete medium), a medium control (7 wellswith medium used to subtract out signal generated by media conditions),a solvent control (8 wells), and an air blank (1 well) for calibratingthe plate reader. Each cell line was also treated with a single dose ofdoxorubicin (1 μM, eight wells) as a positive control for cytotoxicity.Once dosing was completed, the cells were incubated at 37° C. in 5% CO₂and 95% humidity.

Five days after treatment, the cells were analyzed for antineoplasticeffects using the SRB assay to calculate IC₅₀ for each treatment. Theresults are presented in FIG. 2. The results indicate that5-(26-dimethyl-2-heptyl)resorcinol exhibited an IC₅₀ of 77-95 μM in sixcell lines, indicating that such compounds have antineoplastic effects.

In another example, disclosed herein is a method of treatment of and/orpreventing transmission of human immunodeficiency virus (HIV) byadministering to a subject in need thereof a composition comprising acannabinoid derivative. The cannabinoid derivative is, for example,3-Methoxy-5,6,6,9-tetramethyl-5,6,6a,7,8,9,10,10a-octahydro-phenanthridinehaving the formula:

Also disclosed herein is the use of this cannabinoid derivative inpreparing a medicament for treating human immunodeficiency virus (HIV),feline immunodeficiency virus (FIV) and simian immunodeficiency virus(SIV) disease by the indirect inhibition of viral replication throughthe attenuation of the immune response which deprives the virus of thesignals it needs and disrupts the pathways it requires for replication,which results in the slowing of the progression of the disease andprevent acquired immunodeficiency syndrome (AIDS).

In another example, disclosed herein is a method of treatment of and/orpreventing transmission of Human Immunodeficiency Virus (HIV) anddiseases associated with immune dysfunction by administering to asubject in need thereof a composition comprising a cannabinoidderivative. The cannabinoid derivative is, for example,(6aR,10aR)-1-methoxy-6,6-dimethyl-3-(1′,1′-dimethylheptyl)-6a,7,8,9,10,10a-hexahydro-9-methylene-6H-dibenzo[b,d]pyran(L-759656) having the formula:

Also disclosed herein is a method of treating diseases of immunedysfunction comprising autoimmune diseases; further wherein autoimmunediseases comprising systemic lupus erythematosis, Hashimoto'sthyroiditis, Grave's disease, myasthenia gravis, rheumatoid arthritis,multiple sclerosis, Guillan Barre syndrome, glomerulonephritis,polyarteritis nodosa and psoriasis using the cannabinoid derivative(6aR,10aR)-1-methoxy-6,6-dimethyl-3-(1′,1′-dimethylheptyl)-6a,7,8,9,10,10a-hexahydro-9-methylene-6H-dibenzo[b,d]pyran(L-759656). Also disclosed herein is a method of treating diseases whichare a result of inflammation and/or oxidative stress comprising Crohn'sdisease, ulcerative colitis, forms of asthma, cystic fibrosis,Alzheimer's disease, atherosclerosis and associated cardiovasculardiseases using the cannabinoid derivative(6aR,10aR)-1-methoxy-6,6-dimethyl-3-(1′,1′-dimethylheptyl)-6a,7,8,9,10,10a-hexahydro-9-methylene-6H-dibenzo[b,d]pyran(L-759656). Also disclosed herein is a method of treating diseases ofimmune dysfunction which are a result of infectious origin comprisingHuman Immunodeficiency Virus (HIV), Simian Immunodeficiency Virus (SW),Feline Immunodeficiency Virus (FIV), Herpes Simplex virus, Epstein-Barrvirus, Cytomegalovirus, hepatitis B and C, influenza virus, rhinovirusand mycobacterial infections using the cannabinoid derivative(6aR,10aR)-1-methoxy-6,6-dimethyl-3-(1′,1′-dimethylheptyl)-6a,7,8,9,10,10a-hexahydro-9-methylene-6H-dibenzo[b,d]pyran(L-759656). Also disclosed herein is a method of treating and/orpreventing transmission of diseases resulting from a surgical insultsuch as keloids and mesenteric adhesions and prevent allografttransplantation using the cannabinoid derivative(6aR,10aR)-1-methoxy-6,6-dimethyl-3-(1′,1′-dimethylheptyl)-6a,7,8,9,10,10a-hexahydro-9-methylene-6H-dibenzo[b,d]pyran(L-759656).

Also disclosed herein is the use of this cannabinoid derivative(6aR,10aR)-1-methoxy-6,6-dimethyl-3-(1′,1′-dimethylheptyl)-6a,7,8,9,10,10a-hexahydro-9-methylene-6H-dibenzo[b,d]pyran(L-759656) in preparing a medicament for treating HIV, SIV and FIVdisease by the indirect inhibition of viral replication through theattenuation of the immune response which deprives the virus of thesignals it needs and disrupts the pathways it requires for replication,which results in the slowing of the progression of the disease andprevent acquired immunodeficiency syndrome (AIDS). Also disclosed hereinis the use of this cannabinoid derivative in preparing a medicament forthe prevention of HIV, SIV and FIV disease by improving the barrierfunction of the vaginal mucosa by strengthening the integrity of thetight junctions which bind the cells together, by increasing the numberof layers of cells, and by the disruption of the immune responserequired by the viruses required for transmission as mediated throughthe constitutive expression of the CB2 receptors on vaginal epithelialcells and their interaction with immune cells. Also disclosed herein isa pharmaceutical composition comprising a compound(6aR,10aR)-1-methoxy-6,6-dimethyl-3-(1′,1′-dimethylheptyl)-6a,7,8,9,10,10a-hexahydro-9-methylene-6H-dibenzo[b,d]pyran(L-759656), and a pharmaceutically acceptable carrier whether it isadministered by buccal, sublingual, dermal, intraocular, intraotical,pulmonary, transdermal, intralymphatic, intratumor, intracavitary,intranasal, subcutaneous, implantable, inhalable, intradermal, rectal,vaginal, transmucosal, intramuscular, intravenous and intra-articularroutes.

In another example, disclosed herein is a method of treatment of and/orpreventing transmission of Human Immunodeficiency Virus (HIV) anddiseases associated with immune dysfunction by administering to asubject in need thereof a composition comprising a cannabinoidderivative. The cannabinoid derivative is, for example,(6aR,10aR)-1-methoxy-6,6,9-trimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromene(L-759633) having the formula:

Also disclosed herein is a method of treating diseases of immunedysfunction comprising autoimmune diseases; further wherein autoimmunediseases comprising systemic lupus erythematosis, Hashimoto'sthyroiditis, Grave's disease, myasthenia gravis, rheumatoid arthritis,multiple sclerosis, Guillan Barre syndrome, glomerulonephritis,polyarteritis nodosa and psoriasis using the cannabinoid derivative(6aR,10aR)-1-methoxy-6,6,9-trimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromene(L-759633). Also disclosed herein is a method of treating diseases whichare a result of inflammation and/or oxidative stress comprising Crohn'sdisease, ulcerative colitis, forms of asthma, cystic fibrosis,Alzheimer's disease, atherosclerosis and associated cardiovasculardiseases using the cannabinoid derivative(6aR,10aR)-1-methoxy-6,6,9-trimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromene(L-759633). Also disclosed herein is a method of treating diseases ofimmune dysfunction which are a result of infectious origin comprisingHuman Immunodeficiency Virus (HIV), Simian Immunodeficiency Virus (SIV),Feline Immunodeficiency Virus (FIV), Herpes Simplex virus, Epstein-Barrvirus, Cytomegalovirus, hepatitis B and C, influenza virus, rhinovirusand mycobacterial infections using the cannabinoid derivative(6aR,10aR)-1-methoxy-6,6-dimethyl-3-(1′,1′-dimethylheptyl)-6a,7,8,9,10,10a-hexahydro-9-methylene-6H-dibenzo[b,d]pyran(L-759656). Also disclosed herein is a method of treating and/orpreventing transmission of diseases resulting from a surgical insultsuch as keloids and mesenteric adhesions and prevent allografttransplantation using the cannabinoid derivative(6aR,10aR)-1-methoxy-6,6,9-trimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromene(L-759633).

Also disclosed herein is a pharmaceutical composition comprising acompound(6aR,10aR)-1-methoxy-6,6,9-trimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromene(L-759633), and a pharmaceutically acceptable carrier whether it isadministered by buccal, sublingual, dermal, intraocular, intraotical,pulmonary, transdermal, intralymphatic, intratumor, intracavitary,intranasal, subcutaneous, implantable, inhalable, intradermal, rectal,vaginal, transmucosal, intramuscular, intravenous and intra-articularroutes.

Also disclosed herein is the use of this cannabinoid derivative(6aR,10aR)-1-methoxy-6,6,9-trimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromene(L-759633) in preparing a medicament for treating HIV, SIV and FIVdisease by the indirect inhibition of viral replication through theattenuation of the immune response which deprives the virus of thesignals it needs and disrupts the pathways it requires for replication,which results in the slowing of the progression of the disease andprevent acquired immunodeficiency syndrome (AIDS).

Also disclosed herein is the use of this cannabinoid derivative inpreparing a medicament for the prevention of HIV, SIV and FIV disease byimproving the barrier function of the vaginal mucosa by strengtheningthe integrity of the tight junctions which bind the cells together, byincreasing the number of layers of cells and by the disruption of theimmune response required by the viruses for transmission as mediatedthrough the constitutive expression of the CB2 receptors on vaginalepithelial cells and their interaction with immune cells.

In another example, disclosed herein is a method of treatment of and/orpreventing transmission of Human Immunodeficiency Virus (HIV),neoplastic diseases and diseases associated with immune dysfunction byadministering to a subject in need thereof a composition comprising acannabinoid derivative. The cannabinoid derivative is, for example,(±)-trans-3-(1′,1′-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6-6-dimethyl-9H-dibenzo[b,d]pyran-9-one(Cesamet) having the formula:

Also disclosed herein is the use of this cannabinoid derivative,(±)-trans-3-(1′,1′-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6-6-dimethyl-9H-dibenzo[b,d]pyran-9-one(Cesamet) in preparing a medicament for treating HIV, SIV and FIVdisease by the indirect inhibition of viral replication through theattenuation of the immune response which deprives the virus of thesignals it needs and disrupts the pathways it requires for replication,which results in the slowing of the progression of the disease andprevent acquired immunodeficiency syndrome (AIDS).

Also disclosed herein is a pharmaceutical composition comprisingCesamet, and a pharmaceutically acceptable carrier whether it isadministered by buccal, sublingual, dermal, intraocular, intraotical,pulmonary, transdermal, intralymphatic, intratumor, intracavitary,intranasal, subcutaneous, implantable, inhalable, intradermal, rectal,vaginal, transmucosal, intramuscular, intravenous and intra-articularroutes.

In another example, disclosed herein is a method of treatment of and/orpreventing transmission of Human Immunodeficiency Virus (HIV) byadministering to a subject in need thereof a composition comprising acannabinoid derivative. The cannabinoid derivative is, for example,(−)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(Marinol) having the formula:

Also disclosed herein is the use of this cannabinoid derivative(−)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(Marinol) in preparing a medicament for treating HIV, SIV and FIVdisease by the indirect inhibition of viral replication through theattenuation of the immune response which deprives the virus of thesignals it needs and disrupts the pathways it requires for replication,which results in the slowing of the progression of the disease andprevent acquired immunodeficiency syndrome (AIDS).

In another example, disclosed herein is a method of treatment of and/orpreventing transmission of Human Immunodeficiency Virus (HIV) byadministering to a subject in need thereof a composition comprising acannabinoid derivative having the formula shown below:

Also disclosed herein is the use of this cannabinoid derivative inpreparing a medicament for treating HIV, SIV and FIV disease by theindirect inhibition of viral replication through the attenuation of theimmune response which deprives the virus of the signals it needs anddisrupts the pathways it requires for replication, which results in theslowing of the progression of the disease and prevent acquiredimmunodeficiency syndrome (AIDS).

In another example, disclosed herein is a method of treatment of and/orpreventing transmission of human immunodeficiency virus (HIV),neoplastic diseases and diseases associated with immune dysfunction byadministering to a subject in need thereof a composition comprising acannabinoid derivative. The cannabinoid derivative is, for example,(6aR,10aR)-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-Dibenzo(b,d)pyran-9-carboxylicacid (ajulemic acid) having the formula:

Also disclosed herein is a method of treating diseases using thecannabinoid derivative(6aR,10aR)-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-Dibenzo(b,d)pyran-9-carboxylicacid (ajulemic acid), and the use of ajulemic acid in preparing amedicament for treating HIV, SIV and FIV disease by the indirectinhibition of viral replication through the attenuation of the immuneresponse which deprives the virus of the signals it needs and disruptsthe pathways it requires for replication, which results in the slowingof the progression of the disease and prevent acquired immunodeficiencysyndrome (AIDS).

FIGS. 3-18 exemplarily illustrate the results of tests conducted withvarious cannabinoid compounds disclosed herein for increasing thebarrier function of the vagina. The test compounds, namely, L-759,656and L-759,633 were tested at three dilutions (100 μM, 1 μM, and 10 nM)for a 24 hr exposure period and at two dilutions (100 μM and 10 nM) foran extended exposure period of 7 days. The test employed a highlydifferentiated in-vitro vaginal tissue model, EpiVaginal™, VEC-100 fromMatTek Corporation, Ashland, Mass. Tissue viability and transepithelialelectrical resistance (TEER) measurements were performed following theexposure of the EpiVaginal tissues to the test compounds.

FIG. 3 exemplarily illustrates a summary of EpiVaginal tissue viabilityfollowing systemic exposure to the test compounds (test compounds addedto a culture medium) for 24 hrs. FIG. 4 exemplarily illustrates asummary of EpiVaginal tissue viability following the systemic exposureto test compounds (test compounds added to the culture medium) for 7days. The tables of FIGS. 3 and 4 show that the L759,656 and L759,633compounds had minimal effect on the viability of the tissue.

Transepithelial electric resistance (TEER) is a measure of the integrityof the tight junctions which hold the cells together. These junctionsare made up of a variety of proteins which bind the cells together. Inthe context of HIV, the virus causes a breakdown in the tight junctionswhich allows for its translocation across the cells lining the vagina.Therefore, a drug which can maintain or increase the structure andfunction of the tight junctions would therefore increase the barrierfunction of the vaginal tissue and protect against the transmission ofHIV. As noted in the table of FIG. 5, the test compound L759,633exhibited the greatest effect on increasing TEER after a 24 hourexposure period. FIG. 5 exemplarily illustrates a summary of TEERmeasurements following a 24 hr exposure of test compounds to EpiVaginaltissues. FIG. 6 exemplarily illustrates a summary of TEER measurementsfollowing a 7 day exposure period of test compounds to EpiVaginaltissues. The table in FIG. 6 shows that the test compound L759,633 wasas effective in increasing TEER after a seven day exposure period.

FIG. 7 exemplarily illustrates the effect of cannabinoids on tissuethickness following exposure of test compounds to EpiVaginal tissue for7 days. FIG. 8 exemplarily illustrates TEER measurements followingexposure of test compounds to EpiVaginal tissues for 24 hrs. FIG. 9exemplarily illustrates tissue viability and TEER measurements following7 day exposure of the test compounds to the EpiVaginal tissues. FIGS. 8and 9 show the effects on TEER and tissue viability at the highest andthe lowest concentrations of the test compounds used in the experiments.

After the 7 day extended culture period, H&E stained histologicalcross-sections (5-7 μm) of the tissues were made. As illustrated inFIGS. 10 through 18, the thicknesses of cannabinoid-treated anduntreated tissues were measured at three different locations and theaverage tissue thickness was calculated. The result showed that thelowest concentrations of all the test cannabinoids (10 nM) increasedtissue thickness between about 127-147% of the control tissues. At 100μM concentration, only the L-759,633 compound exhibited an increase intissue thickness to about 121.7% of the control tissues. FIG. 10exemplarily illustrates the thickness of EpiVaginal tissues cultured ina medium supplemented with cannabinoid JWH 015 at a concentration of 100μM for 7 days. FIG. 11 exemplarily illustrates the thickness ofEpiVaginal tissues cultured in a medium supplemented with cannabinoidJWH 015 at a concentration of 10 nM for 7 days.

FIG. 12 exemplarily illustrates the thickness of EpiVaginal tissues,cultured in a medium supplemented with cannabinoid L-759,656 at aconcentration of 100 μM for 7 days. FIG. 13 exemplarily illustrates thethickness of EpiVaginal tissues cultured in a medium supplemented withcannabinoid L-759,656 at a concentration of 10 nM for 7 days.

FIG. 14 exemplarily illustrates the thickness of EpiVaginal tissuescultured in a medium supplemented with cannabinoid L-759,633 at aconcentration of 100 μM for 7 days. FIG. 15 exemplarily illustrates thethickness of EpiVaginal tissues cultured in a medium supplemented withcannabinoid L-759,633 at a concentration of 10 nM for 7 days. After theextended culture period, a 10 nM concentration of each of threecannabinoids tested, tissue thickness increased to 147.3%, 136.4%, and127.2% for L-759,633, L-759-656, and JWH-015 compounds, respectively,when compared to the control tissues. At higher concentration (100 μM),L-759,633 compound showed an increase in tissue thickness to about121.7% of the control tissues.

FIG. 16 exemplarily illustrates the thickness of EpiVaginal tissuescultured in a medium supplemented with cannabinoid AM 630 at aconcentration of 100 μM for 7 days. FIG. 17 exemplarily illustrates thethickness of EpiVaginal tissues cultured in a medium supplemented withcannabinoid AM 630 at a concentration of 10 nM for 7 days.

FIG. 18 exemplarily illustrates the thickness of EpiVaginal controltissues (phosphate buffered saline (PBS)) cultured in a medium for 7days.

FIGS. 19-22 exemplarily illustrate the expression levels of thecannabinoid receptors, CB1 and CB2, in the VEC-100 tissue model throughthe use of real time polymerase chain reaction (RT PCR) and effect ofthe three test compounds on the expression of these receptors. Testcompound AM-630 was used as a control. As exemplarily illustrated inFIG. 19, no CB1 expression was noted for negative control or testcompound treated tissues following a 24 hr exposure period. FIG. 20exemplarily illustrates that when the tissues were exposed to testcompounds for 7 days, basal expression was observed and the 100 μMtreated tissues'increased CB1 expression when compared to the negativecontrol tissues. Note that a non-specific band appears on the CB1 gel.

FIG. 21 exemplarily illustrates that CB2 was expressed by the negativecontrol VEC-100 tissue model at the 24 hr exposure time. Up-regulationof CB2 receptor was observed following a 24 hr exposure of tissues toL-759,633 (100 μM) and AM-630 (10 nM). As exemplarily illustrated inFIG. 22, no significant difference in CB2 expression levels was notedbetween the negative control and test compound treated tissues followingthe 7 day exposure period.

Incorporation by Reference

All sources (e.g., inventor's certificates, patent applications,patents, printed-publications, repository accessions or records, utilitymodels, world-wide web pages, and the like) referred to or citedanywhere in this document or in any drawing, Sequence Listing, orStatement filed concurrently herewith are hereby incorporated into andmade part of this specification by such reference thereto, as is thepriority application and International Patent ApplicationPCT/US00/07629, which was published as WO 00/56303.

Guide to Interpretation

The foregoing is an integrated description of the invention as a whole,not merely of any particular element of facet thereof. The descriptiondescribes “preferred embodiments” of this invention, including the bestmode known to the inventors for carrying it out. Of course, upon readingthe foregoing description, variations of those preferred embodimentswill become obvious to those of ordinary skill in the art. The inventorsexpect skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise than asspecifically described herein. Accordingly, this invention includes allmodifications and equivalents of the subject matter recited in theclaims appended hereto as permitted by applicable law.

As used in the foregoing description and in the following claims,singular indicators (e.g., “a” or “one”) include the plural, unlessotherwise indicated. Recitation of a range of discontinuous values isintended to serve as a shorthand method of referring individually toeach separate value falling within the range, and each separate value isincorporated into the specification as if it were individually listed.As regards the claims in particular, the term “consisting essentiallyof” indicates that unlisted ingredients or steps that do not materiallyaffect the basic and novel properties of the invention can be employedin addition to the specifically recited ingredients or steps. Incontrast, the terms “comprising” or “having” indicate that anyingredients or steps can be present in addition to those recited. Theterm “consisting of” indicates that only the recited ingredients orsteps are present, but does not foreclose the possibility thatequivalents of the ingredients or steps can substitute for thosespecifically recited.

1. A method of treatment of and/or preventing transmission of humanimmunodeficiency virus (HIV) by administering to a subject in needthereof a composition comprising a cannabinoid derivative, wherein saidcannabinoid derivative is3-Methoxy-5,6,6,9-tetramethyl-5,6,6a,7,8,9,10,10a-octahydro-phenanthridinehaving the formula:


2. The use of the cannabinoid derivative of claim 1 in preparing amedicament for treating HIV, feline immunodeficiency virus (FIV) andsimian immunodeficiency virus (SIV) disease by indirect inhibition ofviral replication through attenuation of immune response which deprivesthe virus of the signals required by the virus and disrupts the pathwaysrequired by the virus for replication, resulting in slowing progressionof said disease and preventing acquired immunodeficiency syndrome(AIDS).
 3. A method of treatment of and/or preventing transmission ofHuman Immunodeficiency Virus (HIV) and diseases associated with immunedysfunction by administering to a subject in need thereof a compositioncomprising a cannabinoid derivative, wherein said cannanbinoidderivative is(6aR,10aR)-1-methoxy-6,6-dimethyl-3-(1′,1′-dimethylheptyl)-6a,7,8,9,10,10a-hexahydro-9-methylene-6H-dibenzo[b,d]pyran(L-759656) having the formula:


4. A method of treating diseases of immune dysfunction comprisingautoimmune diseases; further wherein autoimmune diseases comprisingsystemic lupus erythematosis, Hashimoto's thyroiditis, Grave's disease,myasthenia gravis, rheumatoid arthritis, multiple sclerosis, GuillanBane syndrome, glomerulonephritis, polyarteritis nodosa and psoriasisusing said cannabinoid derivative of claim
 3. 5. A method of treatingdiseases which are a result of inflammation and/or oxidative stresscomprising Crohn's disease, ulcerative colitis, forms of asthma, cysticfibrosis, Alzheimer's disease, atherosclerosis and associatedcardiovascular diseases using said cannabinoid derivative of claim 3 6.A method of treating diseases of immune dysfunction which are a resultof infectious origin comprising Human Immunodeficiency Virus (HIV),Simian Immunodeficiency Virus, Feline Immunodeficiency Virus, HerpesSimplex virus (Type 1 and 2), Epstein-Barr virus, Cytomegalovirus,hepatitis B and C, influenza virus A and B, respiratory syncitial virus,rhinovirus and mycobacterial infections using said cannabinoidderivative of claim
 3. 7. A method of treating and/or preventingtransmission of diseases resulting from a surgical insult such askeloids and mesenteric adhesions and prevent allograft transplantationusing the cannabinoid derivatives of claim
 3. 8. A pharmaceuticalcomposition comprising a compound according to claim 3 and apharmaceutically acceptable carrier whether it is administered bybuccal, sublingual, dermal, intraocular, intraotical, pulmonary,transdermal, intralymphatic, intratumor, intracavitary, intranasal,subcutaneous, implantable, inhalable, intradermal, rectal, vaginal,transmucosal, intramuscular, intravenous and intra-articular routes. 9.The use of the cannabinoid derivative of claim 3 in preparing amedicament for treating HIV, feline immunodeficiency virus (FIV) andsimian immunodeficiency virus (SIV) disease by indirect inhibition ofviral replication through attenuation of immune response which deprivesthe virus of the signals required by the virus and disrupts the pathwaysrequired by the virus for replication, resulting in slowing progressionof said disease and preventing acquired immunodeficiency syndrome(AIDS).
 10. The use of the cannabinoid derivative of claim 3 inpreparing a medicament for prevention of HIV, SIV and FIV disease byimproving barrier function of vaginal mucosa by strengthening theintegrity of tight junctions which bind the cells together, byincreasing the number of layers of cells, and by disruption of immuneresponse required by the viruses for transmission as mediated throughconstitutive expression of CB2 receptors on vaginal epithelial cells andinteraction of the CB2 receptors with immune cells.
 11. A method oftreatment of and/or preventing transmission of Human ImmunodeficiencyVirus (HIV) and diseases associated with immune dysfunction byadministering to a subject in need thereof a composition comprising acannabinoid derivative, wherein said cannanbinoid derivative is(6aR,10aR)-1-methoxy-6,6,9-trimethyl-3-(2-methyloctan-2-yl)-6a,7,10,10a-tetrahydrobenzo[c]chromene(L-759633) having the formula:


12. A method of treating diseases of immune dysfunction comprisingautoimmune diseases; further wherein autoimmune diseases comprisingsystemic lupus erythematosis, Hashimoto's thyroiditis, Grave's disease,myasthenia gravis, rheumatoid arthritis, multiple sclerosis, GuillanBarre syndrome, glomerulonephritis, polyarteritis nodosa and psoriasisusing said cannabinoid derivative of claim
 11. 13. A method of treatingdiseases which are a result of inflammation and/or oxidative stresscomprising Crohn's disease, ulcerative colitis, forms of asthma, cysticfibrosis, Alzheimer's disease, atherosclerosis and associatedcardiovascular diseases using said cannabinoid derivative of claim 11.14. A method of treating diseases of immune dysfunction which are aresult of infectious origin comprising Human Immunodeficiency Virus(HIV), Simian Immunodeficiency Virus, Feline Immunodeficiency Virus,Herpes Simplex virus (Type 1 and 2), Epstein-Barr virus,Cytomegalovirus, hepatitis B and C, influenza virus (Type A and B),respiratory syncitial virus, rhinovirus and mycobacterial infectionsusing said cannabinoid derivative of claim
 11. 15. A method of treatingand/or preventing transmission of diseases resulting from a surgicalinsult such as keloids and mesenteric adhesions and prevent allografttransplantation using the cannabinoid derivatives of claim
 11. 16. Apharmaceutical composition comprising a compound according to claim 11and a pharmaceutically acceptable carrier whether it is administered bybuccal, sublingual, dermal, intraocular, intraotical, pulmonary,transdermal, intralymphatic, intratumor, intracavitary, intranasal,subcutaneous, implantable, inhalable, intradermal, rectal, vaginal,transmucosal, intramuscular, intravenous and intra-articular routes. 17.The use of the cannabinoid derivative of claim 11 in preparing amedicament for treating HIV, feline immunodeficiency virus (FIV) andsimian immunodeficiency virus (SIV) disease by indirect inhibition ofviral replication through attenuation of immune response which deprivesthe virus of the signals required by the virus and disrupts the pathwaysrequired by the virus for replication, resulting in slowing theprogression of said disease and preventing acquired immunodeficiencysyndrome (AIDS).
 18. The use of the cannabinoid derivative of claim 11in preparing a medicament for prevention of HIV, SIV and FIV disease byimproving barrier function of vaginal mucosa by strengthening theintegrity of tight junctions which bind the cells together, byincreasing the number of layers of cells, and by disruption of immuneresponse required by the viruses for transmission as mediated throughconstitutive expression of CB2 receptors on vaginal epithelial cells andinteraction of the CB2 receptors with immune cells.
 19. A method oftreatment of and/or preventing transmission of Human ImmunodeficiencyVirus (HIV) and diseases associated with immune dysfunction byadministering to a subject in need thereof a composition comprising acannabinoid derivative, wherein said cannanbinoid derivative is(±)-trans-3-(1′,1′-dimethylheptyl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6-6-dimethyl-9H-dibenzo[b,d]pyran-9-one(Cesamet) having the formula:


20. The use of the cannabinoid derivative of claim 19 in preparing amedicament for treating HIV, feline immunodeficiency virus (FIV) andsimian immunodeficiency virus (SIV) disease by indirect inhibition ofviral replication through attenuation of immune response which deprivesthe virus of the signals required by the virus and disrupts the pathwaysrequired by the virus for replication, resulting in slowing progressionof said diseases and preventing acquired immunodeficiency syndrome(AIDS).
 21. A pharmaceutical composition comprising a compound accordingto claim 19 and a pharmaceutically acceptable carrier whether it isadministered by buccal, sublingual, dermal, intraocular, intraotical,pulmonary, transdermal, intralymphatic, intratumor, intracavitary,intranasal, subcutaneous, implantable, inhalable, intradermal, rectal,vaginal, transmucosal, intramuscular, intravenous and intra-articularroutes.
 22. A method of treatment of and/or preventing transmission ofHuman Immunodeficiency Virus (HIV) and diseases associated with immunedysfunction by administering to a subject in need thereof a compositioncomprising a cannabinoid derivative, wherein said cannanbinoidderivative is(−)-(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(Marinol) having the formula:


23. The use of the cannabinoid derivative of claim 22 in preparing amedicament for treating Human Immunodeficiency Virus (HIV), felineimmunodeficiency virus (FIV) and simian immunodeficiency virus (SIV)disease by indirect inhibition of viral replication through attenuationof immune response which deprives the virus of the signals required bythe virus and disrupts the pathways required by the virus forreplication resulting in slowing progression of said disease andpreventing acquired immunodeficiency syndrome (AIDS).
 24. A method oftreatment of and/or preventing transmission of Human ImmunodeficiencyVirus (HIV) disease by administering to a subject in need thereof acomposition comprising a cannabinoid derivative, said cannanbinoidderivative having the formula:


25. The use of the cannabinoid derivative of claim 24 in preparing amedicament for medicament for treating Human Immunodeficiency Virus(HIV), feline immunodeficiency virus (FIV) and simian immunodeficiencyvirus (SIV) disease by indirect inhibition of viral replication throughattenuation of immune response which deprives the virus of the signalsrequired by the virus and disrupts the pathways required by the virusfor replication, resulting in slowing progression of said diseases andpreventing acquired immunodeficiency syndrome (AIDS).
 26. A method oftreatment of and/or preventing transmission of human immunodeficiencyvirus (HIV) by administering to a subject in need thereof a compositioncomprising a cannabinoid derivative, wherein said cannanbinoidderivative is(6aR,10aR)-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-Dibenzo(b,d)pyran-9-carboxylicacid (ajulemic acid) having the formula:


27. The use of the cannabinoid derivative of claim 26 in preparing amedicament for treating Human Immunodeficiency Virus (HIV), felineimmunodeficiency virus (FIV) and simian immunodeficiency virus (SIV)disease by indirect inhibition of viral replication through attenuationof immune response, resulting in slowing progression of said disease andpreventing acquired immunodeficiency syndrome (AIDS).